Research by School

conducting research photo

As you view the pages dedicated to research here at Meharry Medical College you will see a recurring theme: translational research (which we define as research that translates findings into treatments and cures). Also in keeping with trends in research, Meharry’s investigations take a multi-disciplinary approach. Our Centers of Excellence are good examples of this collaborative mindset.

 

In the following links you may view the work of Meharry researchers by discipline. If you notice overlap among these investigations, our centers, our program grants, and other units—then you are noticing a multi-discliplinary, translational research environment. We invite you to collaborate with us.

school of medicine research image

School of Medicine

The researchers in Meharry’s School of Medicine spend their careers serving the medically underserved. They research the diseases that afflict minority communities, and they work to end health care disparities that disproportionally affect the nation’s poor and most vulnerable populations.

MMC and VICC: Partners in eliminating cancer disparities: faculty recruitment

Researcher: Samuel Evans Adunyah, Ph.D.

Funding Source: National Cancer Institute (NCI)

Project Summary: The overall objectives of this project are to strengthen and expand the existing partnership for cancer research between Meharry Medical College (MMC) and the Vanderbilt Ingram Cancer Center (VICC) to achieve three ends: (1) to increase and stabilize the competitive cancer research capability of Meharry; (2) to create stable, long term collaborative relationships between MMC and the VICC in cancer research, research training and career development; (3) to promote, enable and cement a stable, reciprocal, long-term partnership between MMC and VICC based on mutually beneficial research excellence.

The aryl hydrocarbon receptor and breast cancer

Researcher: Sakina Eltom, Ph.D.

Funding Source: National Cancer Institute (NCI)

Project Summary: This study is attempting to define the role AhR plays in invasive breast cancer metastasis, thus establishing it as an independent survival prognostic factor. Studies will also lead to a better understanding of the molecular action of AhR and its ligand-independent activation in advanced breast cancer, thereby providing a unique target for therapeutic interventions.

Pten-loss dysregulated pathways in prostate cancer

Researcher: Zhenbang Chen, Ph.D.

Funding Source: National Minority Health/Health Disparities (NCMHD)

Project Summary: Prostate Cancer (PCa) is the second leading cause of cancer-related deaths (after lung cancer) in American men, and the morbidity and the mortality to PCa are even higher in African American men as compared Caucasians. The goal of this project is to elucidate Pten-loss dysregulated pathways in prostate cancer (PCa) by defining novel roles of p19Arf in prostate cancer progression including castration resistant prostate cancer (CRPC) growth. Results will provide significant insights into understanding of mechanisms on the incidence and the mortality of PCa, and disparities among ethnic and racial groups.

Elucidating binding modes of BRCT-modules

Researcher: Jamaine Davis, Ph.D.

Funding Source: National Cancer Institute (NCI)

Project Summary: There is a fundamental gap in our understanding of how mechanisms of phosphoserine binding modules by BRCT domains enable the assembly of multiprotein DNA repair complexes. Overlooking this gap is an important problem because, until it is solved, understanding how defects in the regulation of DNA repair can potentially cause cancer will remain obscure. The long-term goal is to understand how full-length PTIP regulates the DNA damage response pathway. The objective of this particular application is to provide a molecular description of how PTIP-(BRCT)4 interactions help to regulate DNA repair.

Notch ligands in regulation of anti-cancer immunity

Funding Source: National Cancer Institute (NCI) R01 subcontract

Researcher: Anil Shanker, Ph.D.

Project Summary: Adequate Notch signaling in the immune compartment is critical for the induction of anti-tumor immunity. In this project, in collaboration with Drs. David Carbone and Mikhail Dikov at Ohio State University, the team focuses to achieve a molecular understanding of the roles of Notch, DLL1 and other Notch ligands in anti-tumor T cell immunity. They are also evaluating the therapeutic and prognostic potential that Notch system could offer to enable the translation into clinically relevant cancer therapeutics and prognostic assays.

Eastern Cooperative Oncology Group Clinical Trial (E6508) Laboratory Study: Fraction of immature myeloid cells and dendritic cells

Researcher:Anil Shanker, Ph.D.

Funding Source: Frontier Science & Technology Research Foundation, Inc., EMD Serono, Inc.

Project Summary: Expansion of immunosuppressive immature myeloid cells and inadequate function of dendritic cells is one mechanism of tumor escape from immune system control that may compromise the efficacy of cancer immunotherapy. The goal of this study is to determine the fraction of circulating dendritic cells and immature myeloid cells in blood samples as the prognostic markers of anti-tumor immune status in radiation-treated stage III non-squamous NSCLC lung cancer patients before, during, and after administration with Mucin-1 liposome vaccine (L-BLP25) and the anti-VEGF antibody (bevacizumab).

MMC and VICC: Partners in eliminating cancer disparities: biobaknking managment program (BMaP) (ARRA)

Researcher: Samuel Evans Adunyah, Ph.D.

Funding Source: National Cancer Institute

Project Summary: The overall objectives of this competing continuation application are to strengthen and expand the existing partnership for cancer research between Meharry Medical College (MMC) and the Vanderbilt Ingram Cancer Center (VICC) to achieve three ends: (1) to increase and stabilize the competitive cancer research capability of MMC; (2) to create stable, long term collaborative relationships between MMC and the VICC in cancer research, research training and career development; (3) to promote, enable and cement a stable, reciprocal, long-term partnership between MMC and VICC based on mutually beneficial research excellence.

Mechanisms for B(a)P-induced colon cancer exacerbation by dietary fat

Researcher: Aramandla Ramesh, Ph.D.

Funding Source: National Institute of General Medical Sciences (NIGMS)

Project Summary:This project looks into how environmental toxicants such as benzo(a)pyrene [B(a)P] cause colorectal cancer. It also focuses on how consumption of foods rich in fat accelerates the development of environmentally induced (sporadic) colorectal cancer.

Roles of inflammation-driven chemokines in the pathogenesis of ovarian cancer (SC1)

Researcher: Deok-Soo Son, Ph.D.

Funding Source: National Institute of Allergy/Infectious Diseases (NIAID)

Project Summary: Ovarian cancer is often diagnosed at an advanced stage, after the cancer has spread beyond the ovary, and results in the highest mortality of all cancers of the female reproductive system. Although the precise etiology remains unknown, mounting evidence indicates an impact of inflammation on the development, growth, and progression of ovarian cancer. This project seeks to define the roles of inflammation-driven chemokines in the pathogenesis of ovarian cancer and provide a firm foundation for future long-term survival rates—both for ovarian cancer and other tumors related to inflammation.

Western diet as a modifier of benzo(a)pyrene-induced colon carcinogenesis

Researcher: Kelly Harris, M.S., and Ph.D. candidate

Funding Source: National Institute of Environmental Health Sciences (NIEHS)

Project Summary: Benzo(a)pyrene [B(a)P], an ubiquitous environmental toxicant, is a member of the polycyclic aromatic hydrocarbon (PAH) family of compounds and has been implicated in the causation of colorectal cancer (CRC). Additionally, consumption of red meat and saturated fats, toxicants such as PAHs has also been implicated as one of the risk factors for sporadic colon cancer. Our preliminary studies not only show that B(a)P causes colon cancer, but that administration of Western diet to B(a)P-treated Polyposis increases the development of adenomas in the colon. Our proposed studies will test the hypothesis that Western diet exacerbates B(a)P-initiated colon carcinogenesis through altered biotransformation and DNA damage.

Differentiating Ulcerative Colitis and Crohns Colitis Through Proteomic Patterns

Researcher: Amosy E. M’Koma, M.D., Ph.D.

Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Project Summary: Researchers in Dr. M’Koma’s lab anticipate identifying novel molecular biometric fingerprints that will allow delineation of inflammatory bowel disease called ulcerative colitis (UC) and Crohn’s colitis (CC) as well as potentially predict indeterminate colitis (IC) eventual differentiation into either UC or CC. They hypothesize that these biological signature candidates that distinguish UC from CC and normals represent identifiable proteins that are able to be sequenced and identified.

Defining the effects of bortezomib on NK cell activation in cancer

Funding Source: National Cancer Institute (NCI) SCORE SC1

Researcher: Anil Shanker, Ph.D.

Project Summary: Work in a tumor model demonstrated that along with CD8 T cells, NK cells are indispensable for complete tumor regression, by preventing the development of antigen-deficient tumor escape variants. The major goal of this project is to define the effects of cell-death-sensitizing anti-cancer drug bortezomib on tumor microenvironment and NK cell function in mouse models of cancer.

Regulation of the expression of G[alpha]i2 by reactive oxygen species

Researcher: Ifeanyi J. Arinze, Ph.D.

Funding Source: National Cancer Institute (NCI)

Project Summary: Oxygen radicals, also known as reactive oxygen species (ROS), are products of normal cell metabolism but they are toxic at high levels. They can be induced by drugs, environmental oxidants, and stress-inducing chemicals. ROS and the signal transduction proteins called G proteins are of enormous significance in public health because abnormalities in their function impact many diseases such as diabetes, heart failure, hypertension, atherosclerosis, and cancer. The outcome of Dr. Arinze’s research will contribute to further understanding of these pathologies.

Defective isoforms of ApoE induce atherogenesis via unfolded protein responses

Researcher: Hong Yang, M.D

Funding Source: National Heart, Lung and Blood Institute (NHLBI)

Project Summary: Dr. Yang is studying the involvement of unfolded protein response in foam cell formation, an early stage of atherosclerosis. Data derived from this project will contribute to understanding of the mechanism of atherosclerosis and provide therapeutic strategies for myocardial infarction and stroke induced by atherosclerosis.

Nitric oxide and gastric motility in female diabetics

Researcher: Pandu Gangula, Ph.D.

Funding Source: National Institute of Diabetes/Digestive/Kidney (NIDDK)

Project Summary: Diabetes causes several complications that affect retina, kidney, vascular, gastrointestinal, and nervous system. The mechanism through which diabetic complications develop is unclear. Gastric dysmotility or gastropathy is one of the vigorous complications of diabetic mellitus in clinics and can cause disabling symptoms including nausea, vomiting, and weight loss and often leads to delayed or accelerated gastric emptying. Although the exact pathogenesis remains unknown, there is fairly convincing evidence in experimental models that diabetes results in the malfunctioning of specific neurons that produce the neurotransmitter nitric oxide (NO). The data from Dr. Gangula’s studies will provide important relevant, thereby enhance our understanding of the pathophysiology of gastroparesis.

Effect of antioxidant enzymes on BaP-induced atherogenesis

Researcher: Zhongmao Guo, M.D., Ph.D.

Funding Source: National Institute of Environmental Health Sciences (NIEHS)

Project Summary: Benzo[a]pyrene (BaP) is an environmental pollutant. Besides inducing cancers in humans, BaP has been shown to promote the development of atherosclerosis, which is the primary cause of coronary heart disease and stroke. The mechanism underlying the atherogenic action of BaP remains unknown. A currently popular theory postulates atherosclerosis as an inflammatory process driven by reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. BaP has been shown to increase intracellular ROS. Thus, Dr. Guo’s is looking to see if generation of ROS in vascular cells is a key mechanism by which BaP promotes atherogenesis.

Estrogen-neuroprotection due to astroglial glu transporters occurs via TGF-a/b1

Researcher:Eun-Sook Y. Lee, Ph.D.

Funding Source: National Institute of General Medical Sciences (NIGMS)

Project Summary: Impairment of astroglial glutamate transporters is associated with various neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and manganism, which is caused by chronic manganese (Mn) exposure. Since tamoxifen (TX) and 17B-estradiol (E2) have been shown to be neuroprotective in various neurodegenerative diseases, Dr. Lee is testing whether E2/SERMs can exert neuroprotective effects by attenuating Mn-induced impairment of astroglial glutamate transporters. Moreover, Dr. Lee’s team is testing whether growth factors, TGF-a/B, mediate E2/TX-induced restoration of glutamate transporters.

Human ApoE4 and Foam Cell Formation

Researcher:Zhongmao Guo, M.D., Ph.D.

Project Summary: The overall goal of this project is to determine the mechanism(s) leading to excess cholesterol accumulation in macrophages treated with apolipoprotein E4 (ApoE4)-enriched lipoproteins, and to elucidate the role of unfolded protein response (UPR) in this process. By elucidating the role that ApoE4-containing lipoproteins play in the formation of foam cells, an early event in the development of atherosclerosis, we will provide strategies for treatment or prevention of this disease.

Manipulation of macrophage Alu RNA metabolism by breast cancer cells

Researcher: Gautam Chaudhuri, Ph.D.

Founding source: National Cancer Institute (NCI)

Project Summary: Macrophages are a heterogeneous collection of terminally differentiated mononuclear phagocytes that are distributed all over the mammalian body to perform tissue clearing, tissue remodeling and other functions. These cells act in diverse capacities as the primary responders of our innate and adaptive immune systems. As a part of their tissue clearing roles, macrophages recruited at the site of breast tumor development ingest significant mass of cellular debris formed from the initially dying tumor cells. High levels of phagocytosis induce the production of reactive oxygen and nitrogen species, which in turn elevates the expression of cytotoxic non-coding RNAs (ncRNAs) like Alu RNAs. If not interfered by the tumor cells, high levels of Alu RNA would produce severe inflammatory immune responses through the activation of the inflammasome and accelerated death of the overfed macrophages bringing collateral damage to the breast tumor cells. The preliminary data generated in the PI’s laboratory revealed that during the breast tumor formation, inflammatory development of the recruited macrophages is prevented by breast tumor cells through the reduction of Alu RNA levels in the tumor-associated macrophages converting them to accessory cells supporting tumor growth. We postulate that breast tumor cell-induced reduction in the levels of the cytotoxic Alu RNA in tumor-associated macrophages creates a tissue microenvironment that fosters tumor progression. The long-term goal of the proposed research is to understand how breast tumor cells manipulate macrophages to make them docile and supportive to the development of breast tumors. The central hypothesis is that as a part of the regulation of macrophage turnover, oxidative stress generated during intense phagocytosis by the macrophages at the site of tissue damage (e.g. breast tumor) increases the levels of cytotoxic Alu RNA in these cells. This response in breast tumor-associated macrophages (TAMs) is suppressed by the tumor cells so that these longer-living immune-suppressed macrophages in the tumor microenvironment can be utilized for further development and progression of the breast tumor. Specific Aims to test the hypothesis are: (a) Identification of the mediators secreted from breast cancer cells that manipulate Alu RNA metabolism in the macrophages; and, (b) Evaluation of the mechanisms of manipulation of Alu RNA metabolism in tumor-associated macrophages during breast tumor development. This research proposes an innovative basic mechanism to explain macrophage-assisted breast tumor development highlighting the critical importance of Alu RNAs in the maintenance and disposal of macrophages. The proposed research will make a significant contribution because it will not only highlight a new direction in the understanding of macrophage biology and the etiology of macrophage-associated breast tumor development but also will lead us towards the development of rational chemotherapy against such diseases of the breast.

Structure and Function of the TIM complex in Trypanosoma brucei

Researcher: Minu Chaudhuri, Ph.D.

Founding source:

National Institute of Allergy and Infectious Disease (NIAID)/NIH

1RO1AI117710

Project Summary:

Trypanosoma brucei is the infectious agent of African trypanosomiasis, which is a fatal disease in both humans and livestock. Available therapies are far less than optimal and focus often remains on the single unique mitochondrion possessed by T. brucei as a potential chemotherapeutic target. Mitochondrial functions primarily depend on import of nuclear DNA-encoded proteins. T. brucei possesses a thousand such proteins, therefore it requires a robust import machinery. In contrast to higher eukaryotes, the translocases of mitochondrial outer and inner membranes (TOM and TIM) in T. brucei are highly divergent. Recent studies by our laboratory and others identified a number of non-canonical protein components for this essential cellular process in T. brucei. As part of this machinery, we previously characterized TbTim17, which is critical for mitochondrial protein import and thus essential for parasite survival in both the procyclic and bloodstream forms, the two major developmental forms found in the insect vector and the mammalian bloodstream, respectively. TbTim17 is present in multiple protein complexes within the range of 120-1100 K. Using pull down assays we identified one conserved protein, Tim50, and several other novel proteins. Among these, we found TbTim62, a non-canonical Tim protein, act as a critical assembly factor of the TbTim17 protein complexes and have a major effect on TbTim17 stability. In addition, we found that Tim50 that has a dual-specificity phosphatase activity is involved in an adaptive association with the voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane and plays role in parasite survival during oxidative stress. Based on our preliminary results we hypothesized that TbTims possess unique but critical functions in mitochondrial protein biogenesis as well as participate in the signaling pathway for an adaptive response to cell survival under oxidative stress, which is novel to trypanosomes. We will test this hypothesis by two major aims; 1) determine the unusual and interactive functions of TbTim17, TbTim62 and TbTim50 in T. brucei mitochondrial protein import and 2) elucidate how TbTim50 is involved in the oxidative stress response pathway to maintain cellular homeostasis. We will use many conventional and specialized techniques to evaluate the properties of TbTim17, TbTim62, and TbTim50, including their substrate specificities, ability to assemble the TIM complex, protein-protein interactions, and their essentiality in the bloodstream forms. Using the iTRAQ phosphoproteomic, bioinformatics, and functional genomics analysis we will explore the role of TbTim50 phosphatase on cellular adaptive responses in T. brucei under stress conditions. Together, this knowledge will lay the foundation for developing strategies of an inhibition lethal to the parasite.

Discovery of new anti-amoeba therapeutics

Researcher: Minu Chaudhuri, Ph.D.

Founding source:

National Institute of Allergy and Infectious Disease (NIAID)

R21/R33-subcontract 1R21/R33 AL119782

Project Summary:

Amebiasis and related vision-threatening infections caused by amoebas is a major contributor to diarrheal diseases, primary amoebic meningoencephalitis and cornea problems. Treatment of these infections is challenged by no effective vaccines and limited effective therapeutic options and/or development of resistance. Thus, a need exists for new drugs with more consistent efficacy, less toxicity and exploit the metabolic differences between the parasite and host. Sequencing of amoeba genomes has evoked a broad search for new, pathogen-specific drug targets, of which the sterol C24-methyltransferase (24-SMT) is a clear candidate since it is synthesized in protozoa but not in animals. Notably, 24-SMT is responsible for the introduction of the C1-group into the ergosterol side chain. Although the role of ergosterol and ergosterol biosynthesis enzymes in modulating the infection process from amoeba is poorly understood, our preliminary data of the parasite Trypanosma brucei, whose genome network is similar to the amoeba, revealed that by preventing the biosynthetic renewal of ergosterol augmented protection against infection in a mouse model. In addition, we observed that specific combinations of ergosterol biosynthesis inhibitors were lethal to cell viability. We therefore propose to show ergosterol biosynthesis is required for amoeba cell proliferation and cyst formation, and using one or more agents that selectivity target ergosterol biosynthesis enzymes,24-SMT and sterol 14-demethylase (14-SDM = CYP51), we will show these compounds can produce a disrupted ergosterol homeostasis that thereby, kills cells and provide for better healthcare.

In the R21 phase, we will incubate a series of new mechanism-based inhibitors of ergosterol biosynthesis that differ in the nucleus frame (cycloartenol or obtusifoliol) and electronics of the side chain structure (replace relevant carbon atom with fluorine, sulfur or nitrogen atom) with cultured cells of Acanthamoeba and Naegleria and determine which compounds are the most potent inhibitors of ergosterol biosynthesis, trophozoites growth and cyst formation. Additionally, to make improvements to existing drug therapy we will further evaluate in vitro representative anti-fungal azoles used to treat amoeba infections. These variant inhibitors are designed to inhibit either 24-SMT or 14-SDM action, therefore we will clone [will be performed by our MMC collaborator] and characterize these enzymes kinetically and for product distribution and use them to determine inhibitor specificity, binding and covalent inactivation properties.

The R33 phase will be undertaken with the proof-of-concept demonstrated. We will test in vitro whether our lead molecules that inhibit 24-SMT in combination with traditional chemotherapeutics have synergistic activities. Additionally, in collaboration with Meharry Medical College and UTSoutwestern Medical School, we will evaluate our lead candidate drugs in a mouse model of Acanthamoeba keratitis or primary amebic meningoenchphalitis due to Naegleri fowleri [will be performed by our MMC collaborator]. With the aid of collaborator at Texas Tech University Health Sciences Center, crystal structures of 24-SMT and 14-SDM complexed with relevant inhibitors will be generated to identify binding sites with certainty and should reveal interactions involved with catalysis. ADME/toxicity properties will be evaluated using non-radioactive or 3H-inhibitor fed to healthy mice [will be performed by our MMC collaborator]. Specific steroidal inhibitors determined to possess safe pharmacologic properties would have significant biochemical applications in amoeba chemotherapy.

The overall goal of these studies is to establish mechanism-based inhibitors as a novel class of anti-amoeba agents and to develop therapeutic combinations of drugs (steroidal/ azole inhibitors or these compounds with amphotericin B that target ergosterol biosynthesis and processing to achieve optimal anti-amebiasis effectiveness.

 

Characterizing a small molecule of Streptococcus cristatus for HIV drug design

Researcher: Bindong Liu, Ph.D.

Founding source: National Institute of General Medical Sciences (NIGMS)

Project Summary: The overall number of people living with HIV-1 has continued to increase in all regions of the world. With no prospect for an effective vaccine, containment of the spread of HIV-1 relies on measures to prevent transmission, and treatment relies on antiretroviral therapy. However, drug resistance is becoming increasingly problematic, with some individuals harboring and transmitting viruses that are resistant to a number of different drugs. Thus, an increasing number of people are left with little or no options for new therapeutics. This highlights the need for the development of new antiretroviral agents. We recently discovered that a small molecule of Streptococcus cristatus CC5A (S. cristatus CC5A) is able to up-regulate APOBEC3G and APOBEC3F expression and inhibit HIV replication. This specific research is aimed to characterize this small molecule and to examine the clinical potential of this small molecule in development of novel anti-HIV drugs. We hypothesize that the small molecule of S. cristatus CC5A enhances innate immunity through up- regulation of APOBEC3G and APOBEC3F expression and could be a potential novel anti-HIV drug candidate. To test the hypothesis, we propose following specific aims. (1) To identify and characterize the small molecule of S. cristatus CC5A that promotes A3Fand A3G expression. (2) To exploit the possibility that S. cristatus upregulates APOBEC3 and inhibits HIV replication or transmission in primary HIV target cells, including CD4+ T-cells, macrophages and dendritic cells. (3) To elucidate the mechanism by which this small molecule activates APOBEC3 gene transcription. The successful completion of this proposal will lay the groundwork for developing the small molecule to a novel anti-HIV drug.

Contribution of cellular factor to HIV-1 assembly

Researcher:Xinhong Dong, Ph.D.

Founding source: National Instituteon Minority Health and Health Disparities (NIMHD)

Project Summary:The global HIV epidemic continues to expand exceeding previous predictions and has become one of the deadliest epidemics in human history. The high prevalence of HIV infection in African-American women points to the need to develop new medical interventions toward eliminating women health disparities in HIV/AIDS. The emergence and transmission of HIV-1 isolates resistant to currently approved drugs makes the discovery of novel anti-HIV drugs with new mechanisms and targets a high research priority. HIV-1 Gag protein directs the highly ordered process of particle assembly and release. Distinct steps involved in these late stages of the HIV-1 replication cycle are being defined, yet significant gaps still need to be filled in our knowledge. By yeast two-hybrid screening of a human cDNA library, we identified a novel Gag-binding partner, filamin A. Filamin A (FLNa) is a non-muscle actin binding protein that plays an important role in cross-linking cortical filaments into a dynamic three-dimensional structure. FLNa interacts with different cellular proteins, and serves as a versatile scaffold required for protein trafficking, signaling transduction, and cell-cell and/or cell-matrix connections. The discovery of the FLNa-Gag interaction in a productive manner in HIV-1 particle assembly and release suggests that FLNa facilitates HIV-1 Gag trafficking to the plasma membrane by regulating the actin cytoskeleton remodeling. The overall goal of this research is to define the molecular basis of the FLNa-Gag interaction and its biological significance. Our studies will provide important new information regarding retrovirus-host interactions, and will impact anti-HIV therapy by discovering and developing novel assembly inhibitors. This research proposal will be accomplished in a series of experiments organized within three integrated specific aims. Specific Aim 1: To define the molecular basis of the FLNa-Gag interaction. Specific Aim 2: To define the mechanism of FLNa-regulated HIV-1 Gag trafficking. Specific Aim 3: To define the role of FLNa in human primary CD4+ T cells and macrophages.

Novel Targets for discovering peptide inhibitors of HIV replication

Researcher: Xinhong Dong, Ph.D.

Founding source: National Institute of Allergy and Infectious Diseases (NIAID)

Project Summary: The continual emergence of HIV strains that are resistant to currently approved anti-HIV drugs is an increasing threat to the effective treatment of HIV infection and control of the HIV/AIDS epidemic. Therefore, the discovery and development of new anti-HIV drugs with novel antiviral mechanisms and targets are urgently needed. The long-term objective of this research is to develop a novel class of anti-HIV drugs representing novel chemical entities targeting late stages of the HIV-1 replication cycle. Our recent studies demonstrate a novel protein- protein interaction between HIV-1 Gag and host filamin A, which is involved in late stages of the HIV-1 replication cycle in a productive manner. Disruption of the interaction redistributes Gag subcellular localization and inhibits particle release. These data suggest that the Gag-filamin A interaction could be developed as targets for HIV therapeutics. We hypothesize that small synthetic peptides, containing the binding site required for the interaction, might block specifically the interaction resulting in the impaired virus assembly and release. Experiments will be performed to test this central hypothesis. In specific aim 1, the binding site for Gag and filamin A will be defined by mutagenesis, as well as in vitro and in vivo binding studies. Surface plasmon resonance (SPR) will be used to evaluate the binding kinetics of the interaction. Experiments in specific aim 2 will be designed to identify peptide candidates to specifically block the interaction. Gag- and filamin A-based libraries with overlapping peptide sequences covering the binding site and its surrounding region will be generated.  Screening for peptide candidates against libraries will be performed using direct binding and competitive binding inhibition assays. The binding dynamics of peptide candidates with target proteins will be characterized. In specific aim 3, the role of peptide candidates on virus assembly and release will be examined. Cellular uptake and targeting validation of peptide candidates, which are mediated by Tat peptide, will be evaluated by fluorescence microscopy and flow cytometry. The role of peptide candidates on HIV-1 assembly and release will be determined in human T cell lines, and primary human CD4+ T cells and macrophages. Taken together, these studies will not only provide new sight into retrovirus-host interaction, but also impact the HIV/AIDS therapy by developing novel peptide inhibitors targeting the Gag-filamin A interaction.

Novel trypanosome receptor for Thrombospondin-1

Researcher: Pius N. Nde, Ph.D.

Founding Source: National Institute of Allergy and Infectious Diseases (NIAID)

Project Summary: Trypanosoma cruzi, the causative agent of Chagas heart disease affects several million individuals causing significant morbidity and mortality, yet it remains incurable. T. cruzi modulates the gene expression profiles of a few extracellular matrix proteins to facilitate infection. One of the genes up-regulated early during infection by the parasite is host thrombospondin-1 (TSP-1), a matricellular protein. TSP-1 binds specifically to the surface of invasive forms of T. cruzi trypomastigotes and knockdown of host TSP-1 by RNA interference causing significant inhibition of T. cruzi infection. We hypothesize that the trypomastigote form of T. cruzi up- regulates host TSP-1 that interacts with trypanosome surface receptor(s) to enhance the infection of heart cells. The long-term goal of this research is to understand the molecular mechanisms that allow T. cruzi to infect heart cells, so that specific molecular intervention strategies can be developed to prevent infection of heart cells. This hypothesis will be tested by experiments based on these specific aims: 1. To clone and characterize the novel T. cruzi TSP-1 binding molecule. We will use affinity chromatography, MALDITOF-MS, PCR and purification of recombinant proteins approaches to identify, clone and characterize the trypomastigote receptor that is important in the process of T. cruzi infection; 2. To determine the in vivo role of TSP-1 gene in the process of T. cruzi infection using TSP-1 KO mice model.

Human brain-on-a chip: Regional communication, drug and toxin responses; and Inner blood-retinal barrier-on-a-chip: Implications for ocular disease

Researcher: Donald J. Alcendor, Ph.D.

Funding source: National Center for Advancing Translational Sciences (NCATS)

Project Summary: Physical or pharmacological disruption of chemical signals between the systemic blood flow and the brain impairs normal functioning and responsiveness of the brain. Long-range chemical signaling through dysregulation of cytokines, nutrients, growth factors, hormones, lipids, neurotransmitters, drugs and their metabolites is also important, but these chemical signals are difficult to quantify and cells are usually studied in isolation. The blood-brain barrier (BBB) dynamically controls exchanges between the brain and body, but this cannot be studied directly in the intact human brain or adequately represented by animal models. Most existing in vitro BBB models do not include neurons and glia with other BBB elements and cannot adequately predict drug efficacy and toxicity. This research will develop an in vitro, three-dimensional, multi-compartment, organotypic model of a central nervous system (CNS) neurovascular unit (NVU) and cerebral spinal fluid (CSF) compartment, both coupled to a realistic blood-surrogate supply system that also incorporates circulating immune cells. Primary and stem-cell-derived human cells will interact with a variety of agents to produce critical chemical communications across the BBB and between brain regions, providing a compact device that faithfully reproduces the properties of the human BBB, the CNS, and the CSF. The proposed in vitro BBB/CNS/CSF model will have a small volume, requires a limited number of human cells, can recreate interactions between different brain regions, and will be coupled in real time to advanced electrochemical and mass spectrometry instruments. This transformative technological platform will replicate chemical communication, molecular trafficking, and inflammation in the brain, and will enable targeted and clinically relevant nutritional and pharmacologic interventions or prevention. This platform will be used to examine the role of the BBB in modulating chemical body-brain interactions, characterize glial and neural cell interactions in the brain, and assess the effect of a wide range of drugs, chemicals, infectious agents and xenobiotics on various brain regions. The model’s clinical utility rests on its ability to 1) recreate unique regions by selecting specific combinations of neurons, endothelial cells, astrocytes, other neuroglia, pericytes and systemic leukocytes, 2) use cells and fluids derived from patients with known pathologies to assess drug treatments and physiological stress from chronic diseases such as obesity and acute injury such as stroke, 3) uncover potential adverse effects during drug discovery as well as those that are being used in clinical trials, such as toxic transformation of approved drugs by brain endothelial cells, 4) detect novel and unbiased correlations between large numbers of chemical signals which converge at the BBB, and 5) combine microfluidic devices, state-of-the-art cell culture and organotypic human brain-cell preparations, analytical instruments, bioinformatics, control theory, and neuroscience drug discovery. An integrated approach will provide technologies of widespread applicability and reveal new mechanistic and region-specific insights into how the brain receives, modifies, and is affected by drugs, neurotropic agents and disease. Dr. Alcendor will aid in integration of vascular pericytes of the neurovascular units (NVU) of the blood brain barrier (BBB) and inner blood retinal barriers (IBRB) to develop separate and unique tri-cell culture models. The model of the IBRB will include retinal pericytes, retinal microvascular endothelial cells and Muller cells.  The BBB model will include brain vascular pericytes, brain microvascular endothelial cells and astrocytes. These tri-cell culture models will be incorporated into a microfluidic device modeled after the normal brain and retina that will allow the monitoring of molecular traffic for therapeutic analysis and cellular responses after CMV infection (diseased brain and retina). Dr. Alcendor will interact with Dr. John P. Wikswo’s team at Vanderbilt and grant collaborators from the Cleveland Clinic in the development of these model devices.

Capacity Building Assistance (CBA) to improve the Delivery and Effectiveness of Human Immunodeficiency Virus (HIV) Prevention Services for High-risk and/or Racial/Ethnic Minority Populations

Researcher:  Donald J. Alcendor, Ph.D.

Founding source: Center for Disease Control and Prevention (CDC)

Project Summary: The name of this initiative is Project SAVED – Strengthening Access via Empowerment and Diligence. The overall goal of the project is to strengthen the capacity of African American faith leaders, health providers (trained), Historically Black College and University (HBCU) leaders in metropolitan and non-metropolitan US southern states to collaboratively increase access and the use of HIV prevention services for African American high-risk adolescents and adults (predominantly heterosexual) in their communities utilizing the principles of the Centre for Ethnicity and Health Community Engagement Model. Project SAVED will 1) build SCRET’s capacity to utilize the CEH Community Engagement Model to create opportunities for African American high-risk heterosexuals to access and use HIV prevention services, and 2) build SCRET’s capacity to provide trained CBA members who are able to facilitate and empower community stakeholders to be agents of change by identifying and building upon their assets to increase access to HIV prevention and care services. Their roles and responsibilities will be to: 1) provide guidance and input regarding all aspects and activities of the Project SAVED CBA initiative; 2) undergo master trainer education and receive HIV capacity building training regarding the CEH Model, and to in turn diffuse, adapt, and/or adopt the model within their respective communities; 3) mobilize, identify, and engage persons interested in receiving capacity building information and training; and 4) liaison between Project SAVED staff and community stakeholders.

Structural requirements for sterol 14-alpha-demethylases

Funding source:National Institute of General Medical Sciences (NIGMS) R01 subcontract

Researcher: Fernando Villalta, Ph.D.

Project Summary: Sterol 14α-demethylase (CYP51) is a drug target in lower eukaryotic pathogens such as Trypanosoma cruzi, which causes Chagas disease, because the reaction it catalyzes is essential for membrane formation and therefore loss of this activity is lethal. There are no effective treatments for Chagas disease, which causes significant mortality worldwide and represents a serious global health problem. In this project, in collaboration with Dr. Galina Lepesheva at Vanderbilt University, the team focuses on structure-based development of selective inhibitors for protozoan CYP51s.  They also will synthesize derivatives of the three original scaffolds they discovered that bind to the active site of the enzyme and analyze the efficacy of the best of these derivatives in disease models. The results arising from these studies will lead to rational design of pathogen-selective drugs for the treatment of Chagas disease.

Molecular microbial pathogenesis training program

Researcher:Fernando Villalta, Ph.D.

Funding Source:National Institute of Allergy and Infectious Diseases (NIAID)

Project Summary:   Highly interactive Meharry Medical College and Vanderbilt University mentors who conduct cutting-edge research in molecular microbial pathogenesis participate in this training. The program, for trainees committed to infectious diseases careers, offers trainees opportunities for new discoveries and breakthroughs in the study of the pathogen-host interactions of microbes causing disease including biodefense agents. The innovative features of this program are grounded on cutting-edge science and molecular approaches to study the pathogenesis of microbe-host cell interactions in the following areas: (i) Microbial attachment to receptors, invasion and replication; (ii) Functional genomics and systems biology of microbial infections; (iii) Cell host signaling evoked by pathogens including toxins; (iv) Unique pathogen target genes required for survival; (v) Structural biology and function of new microbial virulent factors; and (vi) Interactions of novel immune molecules with pathogens.

Research training in cardiovascular biology at Meharry

Researcher: Fernando Villalta, Ph.D.

Funding Source: National Heart, Lung and Blood Institute (NHLBI)

Project Summary: This is the third renewal of a NHLBI-supported Minority Institutional Research Training Program in cardiovascular biology at Meharry Medical College (MMC) that will focus in the considerable strengths and diversity of multidepartmental research in cardiovascular biology at MMC and Vanderbilt University School of Medicine (VUMC) into a unique and coherent framework for specialized training. The proposed program will support five pre-doctoral trainees per year and will involve 28 faculty members at MMC and VUMC. Three departments including Cardiovascular Biology at MMC and six departments at VUMC, participate in the program. The research training will focus in cardiovascular biology using cutting edge science and approaches to elucidate mechanisms causing cardiovascular as well as hematologic diseases.

Research Centers in Minority Institutions (RCMI)- Molecular Biology Core Component

Researcher: Robert Holt, Ph.D.

Funding Source: National Institute on Minority Health and Health Disparities (NIMHD)

Project Summary: Dr. Holt is the Scientific Director of the Molecular Biology Core at Meharry Medical College supported by RCMI. This core is a multi-functional facility that provides to faculty, students and staff of the college the primary service of DNA sequencing but also provides access to shared equipment housed in a centralized location and facilitates convenient and rapid access to frequently used molecular biological reagents. This core supports the enhancement of the research enterprise at the College.

Molecular analysis of trypanosome infection

Researcher: Fernando Villalta, Ph.D.

Founding source: National Institute of Allergy and Infectious Diseases  (NIAID)

Project Summary:  Dr. Villalta’s laboratory studies the molecular interface between the human protozoan Trypanosoma cruzi and its host, including the host and pathogen molecules required for intracellular parasitism, mechanisms of pathogenesis and strategies for control. These studies combine a genetics system approach with protein structural analysis, knockout and transgenic animal and parasite models, electron, video and confocal microscopy, functional genomics, gene network analysis and bioinformatics in acute and chronic models of disease.  This research program is aimed to discover the cellular and molecular basis of host cell invasion by T. cruzi and identify the molecular signatures caused by the parasitein host cells leading to pathogenesis and disease. Fundamental questions about the structural basis of molecular interactions involved in the pathogenesis of Chagas disease are being addressed. This work will provide clues to the structure and function of the key virulence factors that are implicated in gastrointestinal and cardiac pathology of Chagas heart disease.

Mechanism based targeted therapies for membranous nephropathy

Researcher: Dorin Bogdan Borza, Ph.D.

Funding Source: Satellite HealthCare, Inc.

Project Summary: Membranous nephropathy (MN) is a major cause of nephrotic syndrome in adults. Up to 40 percent of patients progress to end-stage kidney disease, and another 30 percent suffer from complications of persistent proteinuria and chronic kidney disease. Current therapies are unsatisfactory. Development of much-needed novel therapies require a better understanding of the pathogenic mechanisms. This study will test the hypothesis that the formation of subepithelial immune complexes promoting complement activation via the alternative pathway plays a central role in the pathogenesis of membranous nephropathy, mediating damage to the glomerular filtration barrier and proteinuria. It aims to determine whether targeted therapies specifically inhibiting the activation of the terminal complement cascade or of the alternative pathway , as well as the ablation of plasma cells producing pathogenic antibodies, are effective strategies for ameliorating glomerular damage and proteinuria in animal models of MN. The new knowledge gained from these studies may eventually translate into new treatments for human disease.

Mitochondrial inner membrane protein translocase in trypanosoma brucei

Researcher:Minu Chaudhuri, Ph.D.

Funding Source: National Institute of General Medical Sciences (NIGMS)

Project Summary: African trypanosomiasis, a fatal disease in humans as well as in domestic animals, is caused by the parasitic protozoa, Trypanosoma brucei. As available drugs for this disease are inadequate, it is critical to identify targets to design new drugs. Import of essential mitochondrial proteins is crucial for survival of this parasite in mammalian hosts. Therefore the unique structure and function of mitochondrial protein import molecules could be exploited as novel drug target(s).

Mechanism of biogenesis of atypical alphaviruses

Researcher: Raju Ramasamy, Ph.D.

Funding Source: National Institute of Allergy/Infectious Diseases (NIAID)

Project Summary: Dr. Raju’s long-term goal is to elucidate the pathways of alphavirus RNA genome repair and remodeling leading to the generation of atypical viruses in infected host cells. Alphaviruses are an important cause of emerging viral encephalitides in animals and humans and are significant biodefense agents. Delineating these pathways should lead to strategies to control emergence of outbreaks of alphaviruses and perhaps other mosquito-transmitted RNA viruses. Since alphaviruses are vigorously pursued as gene therapeutic and vaccine delivery vehicles, the team’s work will also be useful in the development of improved RNA vectors.

Control of nociception in the spinal cord (Neurobiology of Pain and Analgesia: Sex-Related Differences)

Researcher: Sukhbir S. Mokha, Ph.D.

Funding Source: National Institute of General Medical Sciences (NIGMS)

Project Summary: Many pain syndromes / disorders such as migraine, trigeminal neuralgia, and irritable bowel syndromes have a higher prevalence in women as compared to men. The goal of our research is to understand the underlying biological mechanisms that make women more vulnerable to the development of pain syndromes and enhance our understanding of the sex-related differences in the regulation of pain throughout the life span. Our research is specifically focused on the genomic and non-genomic effects of sex steroid hormones on the regulation of pain by G protein coupled receptors such as the opioid receptors. Our research will lead to the development of new and better therapeutic strategies for the treatment of pain.

Sleep Disturbance and Adverse Pregnancy Outcomes

Researcher: Sanika Chirwa, Ph.D.

Funding Source: Eunice Kennedy Shriver National Institute of Child Health and Human Development (pending)

Project Summary: The goal of the study is to understand the causal links between poor sleep profiles (i.e. chronic sleep debt, disturbances, and quality) in pregnant women and occurrence of adverse outcomes – e.g. preeclampsia, gestational diabetes, hemorrhage, intra-uterine growth restriction, preterm delivery and macrosomia. We are testing two inter-related hypotheses namely: 1) Sleep disturbance is a potent stressor that independently triggers the release of cortisol. Unbalanced cortisol release, in turn, fosters metabolic abnormalities leading to adverse pregnancy outcomes; and 2) Sleep disturbance will independently attenuate insulin sensitivity, and, thereby, cause impaired glucose tolerance resulting in metabolic abnormalities. The concept that severe sleep disturbance is a potent stressor with the capacity to unbalance the intricate catabolic states that occur in the second half of pregnancy and result in adverse outcomes is innovative. If verified, this will help guide the development of evidence-based screening test(s) for early detection and curtailment of adverse pregnancy outcomes.

Educational and research interventions for the nuclear regulatory commission

Researcher: Clivel Charlton, Ph.D.

Funding Source: Nuclear Regulatory Commission

Project Summary: The ultimate goal of activities conducted under this activity seek to establish scientific research programs with Y12 National Security Complex scientists to better understand the consequences of nuclear fallout disposition to the developing central nervous system and subsequent effects on cognitive processes in vulnerable military populations. Activities under this award will also serve to provide a customized pipeline for minority biomedical scientist and occupational and environmental medicine positions at Y12, Oak Ridge National Laboratory and other national security complexes.

In Utero Exposure to Methamphetamine: Risks and Adverse Outcomes in Progeny

Researcher: Sanika Chirwa, Ph.D.

Funding Source: National Institute of Drug Abuse (pending)

Project Summary: The goal of this project is to understand in detail the risks and attendant cognitive-behavioral dysfunctions in off-springs exposed to methamphetamine in utero. The project entails using behavior tests for episodic memory (i.e. novel object recognition) coupled with in vivo electrophysiological recordings for studying synaptic plasticity and neural network interactions in the hippocampus, a brain structure that is critical for episodic memory acquisition and consolidation. Data from this project will help clarify how and by what mechanisms exposure to methamphetamine in utero subsequently affects mnemonic functions in off-springs.

Sex-based and individual-based differences in the comorbidity of drug addiction and mood disorders.

Researcher: Akiko Shimamoto, Ph.D.

Funding Source: Research Centers in Minority Institutions (RCMI)

Project Summary: This project investigates molecular, neuronal, and behavioral mechanisms underlying chronic stress-induced addictive behaviors in both males and females. The main focus of this project is brain reward pathway, including dopamine, glutamate, and GABA neurons. The proposed research will help us understand how drug addiction is influenced by mood disorders such as depression, and will lead to a more effective treatment for these individuals.

Residency Training in Primary Care

Researcher: Millard D. Collins, M.D.

Funding Source: Health Resources and Services Administration (HRSA)

Project Summary: The program will improve and transform two residency programs –Public Health/General Preventive Medicine (PH/GPM) and Occupational Medicine (OM) at Meharry Medical College. Both programs are Accreditation Council for Graduate Medical Education (ACGME) -accredited, and the OM program is the only such residency at a Historically Black College or University in the United States. The program has 16 specific objectives, the sum of which will assure that over a five-year period, 26 residents acquire all ACGME required competencies. The goal of improvement will be accomplished, in part, by providing broader opportunities for residents to work in community health centers, community hospitals, and state and local health departments with emphasis on integrating primary care and preventive medicine. The goal of transformation will address the need for preventive medicine physicians to become better advocates for their role as professionals. Prevention Leadership Advocacy Rotations will result in improved understanding of how the totality of medical evidence is currently managed by legislators and public health physicians, how unintended adverse effects of legislative decisions are currently communicated to populations at risk, and what implications this holds for both preventive medicine practice and residents’ choices regarding their own career paths. Residents will also attend intensive training in Bioethics at the National Center for Bioethics at Tuskegee University in Tuskegee, Alabama.

Southeast Fetal Alcohol Spectrum Disorders Regional Training Center

Researcher: Heather O’Hara, M.D.

Funding Source: Centers for Disease Control and Prevention (CDC)

Project Summary: The major goal of this project is to establish and operate a center for the recognition, training and prevention of fetal alcohol syndrome, and research on this subject.

Pre-doctoral training in Primary Care

Researcher: Millard D. Collins, M.D.

Funding Source: Health Resources and Services Administration (HRSA)

Project Summary: This program will enhance the student training experience in primary care by creating a student health disparity scholar track, adding adolescent medicine curriculum, and introducing evidence based medical education.

Pre-doctoral training in Primary Care

Researcher: Millard D. Collins, M.D.

Funding Source: Health Resources and Services Administration (HRSA)

Project Summary: This program will enhance the student training experience in primary care by creating a student health disparity scholar track, adding adolescent medicine curriculum, and introducing evidence based medical education.

Screening Brief Intervention and Referral to Treatment (SBIRT)

Researcher: Marquetta L. Faulkner, M.D., M.B.A., F.A.C.P., F.A.S.N.

Funding Source: Department of Human Health Services/SAMHSA

Project Summary: The Internal Medicine Primary Care Clinic of Nashville General Hospital at Meharry (PCC) implements the Screening, Brief Intervention, and Referral to Treatment initiative (SBIRT). The focus of SBIRT is to screen individuals visiting the PCC to proactively address risky alcohol and/or drug use in clients before those risky behaviors become a more serious problem. Research has shown that intervening early with individuals at moderate risk is effective in reducing substance use, preventing co-morbid health conditions, and reducing health care costs. In addition, SBIRT provides support for our primary care attending clinics and training for our residents in our Internal Medicine Residency Program.

Meharry Community Wellness Center (Ryan White Part C outpatient EIS program)

Researcher:Vladimir Berthaud, M.D., M.P.H., F.A.C.P.

Funding Source:Health Resources and Services Administration

Project Summary:This HIV/AIDS program includes a wide range of early intervention services and focuses on expanding access to and retention into high quality care, reducing health disparities, and improving health outcomes. The target population (African Americans in north Nashville) are characterized by high rates of non-insurance (43%), poverty (87.5%), incarceration (20%), low education (86%), and family breakdown (85%). Among clients seen at MCWC, the primary mode of transmission is heterosexual contact (56%) but MSM category is increasing (23%). The primary goals of this program are 1) to reduce the rate of HIV/AIDS and 2) to improve the health outcomes of low-income and medically underserved African Americans living with HIV/AIDS primarily in North Nashville.

The Meharry Medical College (MMC) and the Vanderbilt-lngram Cancer Center (VICC): partnering for survivorship

Researcher:John J. Murray, M.D., Ph.D.

Funding Source: National Cancer Institute (NCI)

Project Summary: The Meharry Medical College (MMC) and the Vanderbilt-lngram Cancer Center (VICC) Survival from cancer in adults now exceeds 65 percent, although disparities exist between African Americans and Caucasians for reasons that are only partly understood. With this growing cohort of survivors, little research has been conducted to assess long-term outcomes, especially among cancer survivors and particularly in minority survivor populations where baseline health disparities exists. A partnership between Vanderbilt-lngram Cancer Center and Meharry Medical College is addressing the lack of data.

Meharry Medical College-CHC Community Networks Program Center

Researcher:Margaret Hargreaves, Ph.D.

Funding Source:National Institutes of Health

Project Summary: The purpose of the Meharry Medical College-Community Health Centers (CHCs) Community Networks Program (CNP) is to reduce cancer health disparities among African Americans by conducting community-based participatory research in select urban and rural communities in Tennessee (Nashville, Chattanooga, Memphis) and Mississippi (Jackson, Canton, Mound, Bayou). Overall program goals are to significantly improve access to and utilization of beneficial cancer interventions in these CHC communities and provide a cadre of well trained researchers who continue to reduce disparities in these communities. An umbrella coalition of organizations and individuals has been formed to make joint plans for community networking activities and to develop an infrastructure that facilitates research participation in the target population. Meharry serves as the Coordinating Center.

Mammographic breast density in a cohort of medically underserved women.

Researcher: Maureen Sanderson, M.P.H., R.D., Ph.D.

Funding Source: Department of Defense (DOD)

Project Summary: This research project investigates the relationships between hormones, diet, body size, and mammographic breast density among underserved women.

Rapid weight gain prevention in African American infants

Researcher: Flora Ukoli, M.D., M.P.H.

Funding Source: Center for Medicare and Medicaid Services (CMS)

Project Summary: Childhood obesity disproportionately affects low-income minority children. Up to 25 percent of U.S. pre-school children are overweight. Rapid weight gain (RWG) in the first year of life, an important predictor of childhood obesity, can be prevented by healthy infant feeding patterns that include exclusive breastfeeding (EBF) for 6 months, breastfeeding up till the second birthday, and restriction of high-calorie beverages. The goal of this study is to prepare mothers to prevent childhood obesity through an education intervention that will help mothers to make healthy infant feeding choices and adopt proper breastfeeding practices. This project is significant as it addresses two important public health concerns, childhood obesity prevention and breastfeeding practices, both of which are in line with the mission of the Centers for Medicare and Medicaid Services. These health issues are extremely relevant in the state of Tennessee because the state records one of the highest obesity rates and one of the lowest breastfeeding rates in the nation, particularly among African-Americans.  The most vulnerable infants are those born to low-income, low-educated and young mothers. This is a pre-test post-test non-randomized intervention that will utilize the Community-Based Participatory Research approach to develop a culturally appropriate childhood obesity prevention education intervention in partnership with a community advisory board of lay African-American mothers in Nashville.

Meharry-John Hopkins center for prostate cancer research

Researcher: Flora Ukoli, M.D., M.P.H.

Funding Source: Department of Defense (DOD)

Project Summary: The burden associated with prostate cancers falls disproportionately on African American men. The prostate cancer incidence rate among African American men is 55 percent greater than that of Caucasian men, and according to the National Cancer Institute (NCI) state cancer profiles, the mortality rate is almost three time that of Caucasian men (73.9 per 100,000 African American/25.6 per 100,000 Caucasian). Genetic and dietary factors have been identified in explaining a portion of the excess burden experienced by African American men, yet we have been unable to identify risk factors that are both of substantial magnitude and amenable to preventive intervention. This study will combine qualitative and quantitative research techniques to assess the knowledge, attitudes, and preventive practices of adult sons (“sons”) of men with prostate cancer (“fathers”). It will be conducted in parallel with the examination of men with prostate cancer (The Fathers Study”), the goals of which are (1) to investigate the effects of race, economic status, and psycho-social factors on the quality of life of men diagnosed with prostate cancer; (2) to investigate psycho-social factors that influence help seeking behavior among men who were diagnosed with prostate cancer; and (3) to examine the effects of informed decision-making and knowledge on prostate cancer treatment decision-making. The Principal Investigator for the project is Dr. Thomas LaVeist of Johns Hopkins University and Meharry’s Dr. Flora Ukoli is the Co-Principal Investigator.

Prostate cancer education and screening pilot program for African Americans

Researcher: Flora Ukoli, M.D., M.P.H.

Funding Source: National Cancer Institute (NCI)

Project Summary: African-American men bear an unequal burden for prostate cancer (PCa) compared to other ethnic and racial groups. Dr. Ukoli hopes to reduce this burden by improving PCa knowledge and encouraging informed screening decisions among low-income African-American men.

Community partnership to reduce the diabetes/obesity burden among African American women in Nashville, Tenn. (MeTRC)

Researcher: Stephania T. Miller-Hughes, Ph.D

Funding Source: National Center for Research Resources (NCRR)

Project Summary: Working with Mt. Zion Baptist Church and the Full Circle Healthy Community Coalition, this project plans to test a peer-support technique to help women with very little time for themselves better manage their weight and Type 2 diabetes.

Prostate cancer research training in health disparities for minority undergraduates

Researcher: Flora Ukoli, M.D., M.P.H.

Funding Source: Department of Defense (DOD)

Project Summary: African-American men have the highest prostate cancer (PCa) incidence in the world and their mortality rate is approximately 2-fold higher than that for American whites. The need to build a formidable team of multidisciplinary researchers that cut across ethnic and generational groups cannot be over emphasized. Pre-doctoral and post-doctoral programs are limited to large universities and may not be accessible to undergraduates from small colleges and HBCUs because of their highly competitive nature. The aim of Dr. Ukoli’s program is to identify enthusiastic, intelligent, and talented HBCU undergraduates  at  Fisk  University  in  Nashville and  pair  them  with  role  model research faculty at Meharry and Vanderbilt University to undergo an exciting summer research training program and thereby attract them to careers in PCa disparity research.

School of Dentistry

The research vision of the School of Dentistry is to ensure research training is fully integrated within the academic programs and encouraging our faculty and students to be fully engaged in research activities. The plans for developing a research infrastructure to foster and facilitate interdisciplinary research and research training are underway.

Part of the plan includes developing a Research Advisory Council (RAC) that advises the associate dean on research priorities, policies, procedures, and guides decision-making on additional resources needed. The RAC will create a strategic plan that establishes a clear, quantifiable research program with funding goals that address the needs of the School of Dentistry.

revision of School of Medicine research photo

School of Graduate Studies and Research

The researchers in Meharry’s School of Medicine spend their careers serving the medically underserved. They research the diseases that afflict minority communities, and they work to end health care disparities that disproportionally affect the nation’s poor and most vulnerable populations.

MMC and VICC: Partners in eliminating cancer disparities: faculty recruitment

Researcher: Samuel Evans Adunyah, Ph.D.

Funding Source: National Cancer Institute (NCI)

Project Summary: The overall objectives of this project are to strengthen and expand the existing partnership for cancer research between Meharry Medical College (MMC) and the Vanderbilt Ingram Cancer Center (VICC) to achieve three ends: (1) to increase and stabilize the competitive cancer research capability of Meharry; (2) to create stable, long term collaborative relationships between MMC and the VICC in cancer research, research training and career development; (3) to promote, enable and cement a stable, reciprocal, long-term partnership between MMC and VICC based on mutually beneficial research excellence.

The aryl hydrocarbon receptor and breast cancer

Researcher: Sakina Eltom, Ph.D.

Funding Source: National Cancer Institute (NCI)

Project Summary: This study is attempting to define the role AhR plays in invasive breast cancer metastasis, thus establishing it as an independent survival prognostic factor. Studies will also lead to a better understanding of the molecular action of AhR and its ligand-independent activation in advanced breast cancer, thereby providing a unique target for therapeutic interventions.

Roles of inflammation-driven chemokines in the pathogenesis of ovarian cancer (SC1)

Researcher: Deok-Soo Son, Ph.D.

Funding Source: National Institute of Allergy/Infectious Diseases (NIAID)

Project Summary: Ovarian cancer is often diagnosed at an advanced stage, after the cancer has spread beyond the ovary, and results in the highest mortality of all cancers of the female reproductive system. Although the precise etiology remains unknown, mounting evidence indicates an impact of inflammation on the development, growth, and progression of ovarian cancer. This project seeks to define the roles of inflammation-driven chemokines in the pathogenesis of ovarian cancer and provide a firm foundation for future long-term survival rates—both for ovarian cancer and other tumors related to inflammation.

Elucidating binding modes of BRCT-modules

Researcher: Jamaine Davis, Ph.D.

Funding Source: National Cancer Institute (NCI)

Project Summary: There is a fundamental gap in our understanding of how mechanisms of phosphoserine binding modules by BRCT domains enable the assembly of multiprotein DNA repair complexes. Overlooking this gap is an important problem because, until it is solved, understanding how defects in the regulation of DNA repair can potentially cause cancer will remain obscure. The long-term goal is to understand how full-length PTIP regulates the DNA damage response pathway. The objective of this particular application is to provide a molecular description of how PTIP-(BRCT)4 interactions help to regulate DNA repair.

Notch ligands in regulation of anti-cancer immunity

Funding Source: National Cancer Institute (NCI) R01 subcontract

Researcher: Anil Shanker, Ph.D.

Project Summary: Adequate Notch signaling in the immune compartment is critical for the induction of anti-tumor immunity. In this project, in collaboration with Drs. David Carbone and Mikhail Dikov at Ohio State University, the team focuses to achieve a molecular understanding of the roles of Notch, DLL1 and other Notch ligands in anti-tumor T cell immunity. They are also evaluating the therapeutic and prognostic potential that Notch system could offer to enable the translation into clinically relevant cancer therapeutics and prognostic assays.

Eastern Cooperative Oncology Group Clinical Trial (E6508) Laboratory Study: Fraction of immature myeloid cells and dendritic cells

Researcher:Anil Shanker, Ph.D.

Funding Source: Frontier Science & Technology Research Foundation, Inc., EMD Serono, Inc.

Project Summary: Expansion of immunosuppressive immature myeloid cells and inadequate function of dendritic cells is one mechanism of tumor escape from immune system control that may compromise the efficacy of cancer immunotherapy. The goal of this study is to determine the fraction of circulating dendritic cells and immature myeloid cells in blood samples as the prognostic markers of anti-tumor immune status in radiation-treated stage III non-squamous NSCLC lung cancer patients before, during, and after administration with Mucin-1 liposome vaccine (L-BLP25) and the anti-VEGF antibody (bevacizumab).

MMC and VICC: Partners in eliminating cancer disparities: biobaknking managment program (BMaP) (ARRA)

Researcher: Samuel Evans Adunyah, Ph.D.

Funding Source: National Cancer Institute

Project Summary: The overall objectives of this competing continuation application are to strengthen and expand the existing partnership for cancer research between Meharry Medical College (MMC) and the Vanderbilt Ingram Cancer Center (VICC) to achieve three ends: (1) to increase and stabilize the competitive cancer research capability of MMC; (2) to create stable, long term collaborative relationships between MMC and the VICC in cancer research, research training and career development; (3) to promote, enable and cement a stable, reciprocal, long-term partnership between MMC and VICC based on mutually beneficial research excellence.

Mechanisms for B(a)P-induced colon cancer exacerbation by dietary fat

Researcher: Aramandla Ramesh, Ph.D.

Funding Source: National Institute of General Medical Sciences (NIGMS)

Project Summary:This project looks into how environmental toxicants such as benzo(a)pyrene [B(a)P] cause colorectal cancer. It also focuses on how consumption of foods rich in fat accelerates the development of environmentally induced (sporadic) colorectal cancer.

Pten-loss dysregulated pathways in prostate cancer

Researcher: Zhenbang Chen, Ph.D.

Funding Source: National Minority Health/Health Disparities (NCMHD)

Project Summary: Prostate Cancer (PCa) is the second leading cause of cancer-related deaths (after lung cancer) in American men, and the morbidity and the mortality to PCa are even higher in African American men as compared Caucasians. The goal of this project is to elucidate Pten-loss dysregulated pathways in prostate cancer (PCa) by defining novel roles of p19Arf in prostate cancer progression including castration resistant prostate cancer (CRPC) growth. Results will provide significant insights into understanding of mechanisms on the incidence and the mortality of PCa, and disparities among ethnic and racial groups.

Western diet as a modifier of benzo(a)pyrene-induced colon carcinogenesis

Researcher: Kelly Harris, M.S., and Ph.D. candidate

Funding Source: National Institute of Environmental Health Sciences (NIEHS)

Project Summary: Benzo(a)pyrene [B(a)P], an ubiquitous environmental toxicant, is a member of the polycyclic aromatic hydrocarbon (PAH) family of compounds and has been implicated in the causation of colorectal cancer (CRC). Additionally, consumption of red meat and saturated fats, toxicants such as PAHs has also been implicated as one of the risk factors for sporadic colon cancer. Our preliminary studies not only show that B(a)P causes colon cancer, but that administration of Western diet to B(a)P-treated Polyposis increases the development of adenomas in the colon. Our proposed studies will test the hypothesis that Western diet exacerbates B(a)P-initiated colon carcinogenesis through altered biotransformation and DNA damage.

Differentiating Ulcerative Colitis and Crohns Colitis Through Proteomic Patterns

Researcher: Amosy E. M’Koma, M.D., Ph.D.

Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Project Summary: Researchers in Dr. M’Koma’s lab anticipate identifying novel molecular biometric fingerprints that will allow delineation of inflammatory bowel disease called ulcerative colitis (UC) and Crohn’s colitis (CC) as well as potentially predict indeterminate colitis (IC) eventual differentiation into either UC or CC. They hypothesize that these biological signature candidates that distinguish UC from CC and normals represent identifiable proteins that are able to be sequenced and identified.

Defining the effects of bortezomib on NK cell activation in cancer

Funding Source: National Cancer Institute (NCI) SCORE SC1

Researcher: Anil Shanker, Ph.D.

Project Summary: Work in a tumor model demonstrated that along with CD8 T cells, NK cells are indispensable for complete tumor regression, by preventing the development of antigen-deficient tumor escape variants. The major goal of this project is to define the effects of cell-death-sensitizing anti-cancer drug bortezomib on tumor microenvironment and NK cell function in mouse models of cancer.

Regulation of the expression of G[alpha]i2 by reactive oxygen species

Researcher: Ifeanyi J. Arinze, Ph.D.

Funding Source: National Cancer Institute (NCI)

Project Summary: Oxygen radicals, also known as reactive oxygen species (ROS), are products of normal cell metabolism but they are toxic at high levels. They can be induced by drugs, environmental oxidants, and stress-inducing chemicals. ROS and the signal transduction proteins called G proteins are of enormous significance in public health because abnormalities in their function impact many diseases such as diabetes, heart failure, hypertension, atherosclerosis, and cancer. The outcome of Dr. Arinze’s research will contribute to further understanding of these pathologies.

Defective isoforms of ApoE induce atherogenesis via unfolded protein responses

Researcher: Hong Yang, M.D

Funding Source: National Heart, Lung and Blood Institute (NHLBI)

Project Summary: Dr. Yang is studying the involvement of unfolded protein response in foam cell formation, an early stage of atherosclerosis. Data derived from this project will contribute to understanding of the mechanism of atherosclerosis and provide therapeutic strategies for myocardial infarction and stroke induced by atherosclerosis.

Nitric oxide and gastric motility in female diabetics

Researcher: Pandu Gangula, Ph.D.

Funding Source: National Institute of Diabetes/Digestive/Kidney (NIDDK)

Project Summary: Diabetes causes several complications that affect retina, kidney, vascular, gastrointestinal, and nervous system. The mechanism through which diabetic complications develop is unclear. Gastric dysmotility or gastropathy is one of the vigorous complications of diabetic mellitus in clinics and can cause disabling symptoms including nausea, vomiting, and weight loss and often leads to delayed or accelerated gastric emptying. Although the exact pathogenesis remains unknown, there is fairly convincing evidence in experimental models that diabetes results in the malfunctioning of specific neurons that produce the neurotransmitter nitric oxide (NO). The data from Dr. Gangula’s studies will provide important relevant, thereby enhance our understanding of the pathophysiology of gastroparesis.

Effect of antioxidant enzymes on BaP-induced atherogenesis

Researcher: Zhongmao Guo, M.D., Ph.D.

Funding Source: National Institute of Environmental Health Sciences (NIEHS)

Project Summary: Benzo[a]pyrene (BaP) is an environmental pollutant. Besides inducing cancers in humans, BaP has been shown to promote the development of atherosclerosis, which is the primary cause of coronary heart disease and stroke. The mechanism underlying the atherogenic action of BaP remains unknown. A currently popular theory postulates atherosclerosis as an inflammatory process driven by reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. BaP has been shown to increase intracellular ROS. Thus, Dr. Guo’s is looking to see if generation of ROS in vascular cells is a key mechanism by which BaP promotes atherogenesis.

Estrogen-neuroprotection due to astroglial glu transporters occurs via TGF-a/b1

Researcher:Eun-Sook Y. Lee, Ph.D.

Funding Source: National Institute of General Medical Sciences (NIGMS)

Project Summary: Impairment of astroglial glutamate transporters is associated with various neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and manganism, which is caused by chronic manganese (Mn) exposure. Since tamoxifen (TX) and 17B-estradiol (E2) have been shown to be neuroprotective in various neurodegenerative diseases, Dr. Lee is testing whether E2/SERMs can exert neuroprotective effects by attenuating Mn-induced impairment of astroglial glutamate transporters. Moreover, Dr. Lee’s team is testing whether growth factors, TGF-a/B, mediate E2/TX-induced restoration of glutamate transporters.

Human ApoE4 and Foam Cell Formation

Researcher:Zhongmao Guo, M.D., Ph.D.

Project Summary: The overall goal of this project is to determine the mechanism(s) leading to excess cholesterol accumulation in macrophages treated with apolipoprotein E4 (ApoE4)-enriched lipoproteins, and to elucidate the role of unfolded protein response (UPR) in this process. By elucidating the role that ApoE4-containing lipoproteins play in the formation of foam cells, an early event in the development of atherosclerosis, we will provide strategies for treatment or prevention of this disease.

Manipulation of macrophage Alu RNA metabolism by breast cancer cells

Researcher: Gautam Chaudhuri, Ph.D.

Funding source: National Cancer Institute (NCI)

Project Summary: Macrophages are a heterogeneous collection of terminally differentiated mononuclear phagocytes that are distributed all over the mammalian body to perform tissue clearing, tissue remodeling and other functions. These cells act in diverse capacities as the primary responders of our innate and adaptive immune systems. As a part of their tissue clearing roles, macrophages recruited at the site of breast tumor development ingest significant mass of cellular debris formed from the initially dying tumor cells. High levels of phagocytosis induce the production of reactive oxygen and nitrogen species, which in turn elevates the expression of cytotoxic non-coding RNAs (ncRNAs) like Alu RNAs. If not interfered by the tumor cells, high levels of Alu RNA would produce severe inflammatory immune responses through the activation of the inflammasome and accelerated death of the overfed macrophages bringing collateral damage to the breast tumor cells. The preliminary data generated in the PI’s laboratory revealed that during the breast tumor formation, inflammatory development of the recruited macrophages is prevented by breast tumor cells through the reduction of Alu RNA levels in the tumor-associated macrophages converting them to accessory cells supporting tumor growth. We postulate that breast tumor cell-induced reduction in the levels of the cytotoxic Alu RNA in tumor-associated macrophages creates a tissue microenvironment that fosters tumor progression. The long-term goal of the proposed research is to understand how breast tumor cells manipulate macrophages to make them docile and supportive to the development of breast tumors. The central hypothesis is that as a part of the regulation of macrophage turnover, oxidative stress generated during intense phagocytosis by the macrophages at the site of tissue damage (e.g. breast tumor) increases the levels of cytotoxic Alu RNA in these cells. This response in breast tumor-associated macrophages (TAMs) is suppressed by the tumor cells so that these longer-living immune-suppressed macrophages in the tumor microenvironment can be utilized for further development and progression of the breast tumor. Specific Aims to test the hypothesis are: (a) Identification of the mediators secreted from breast cancer cells that manipulate Alu RNA metabolism in the macrophages; and, (b) Evaluation of the mechanisms of manipulation of Alu RNA metabolism in tumor-associated macrophages during breast tumor development. This research proposes an innovative basic mechanism to explain macrophage-assisted breast tumor development highlighting the critical importance of Alu RNAs in the maintenance and disposal of macrophages. The proposed research will make a significant contribution because it will not only highlight a new direction in the understanding of macrophage biology and the etiology of macrophage-associated breast tumor development but also will lead us towards the development of rational chemotherapy against such diseases of the breast.

Structure and Function of the TIM complex in Trypanosoma brucei

Researcher: Minu Chaudhuri, Ph.D.

Funding source:

National Institute of Allergy and Infectious Disease (NIAID)/NIH

1RO1AI117710

Project Summary:

Trypanosoma brucei is the infectious agent of African trypanosomiasis, which is a fatal disease in both humans and livestock. Available therapies are far less than optimal and focus often remains on the single unique mitochondrion possessed by T. brucei as a potential chemotherapeutic target. Mitochondrial functions primarily depend on import of nuclear DNA-encoded proteins. T. brucei possesses a thousand such proteins, therefore it requires a robust import machinery. In contrast to higher eukaryotes, the translocases of mitochondrial outer and inner membranes (TOM and TIM) in T. brucei are highly divergent. Recent studies by our laboratory and others identified a number of non-canonical protein components for this essential cellular process in T. brucei. As part of this machinery, we previously characterized TbTim17, which is critical for mitochondrial protein import and thus essential for parasite survival in both the procyclic and bloodstream forms, the two major developmental forms found in the insect vector and the mammalian bloodstream, respectively. TbTim17 is present in multiple protein complexes within the range of 120-1100 K. Using pull down assays we identified one conserved protein, Tim50, and several other novel proteins. Among these, we found TbTim62, a non-canonical Tim protein, act as a critical assembly factor of the TbTim17 protein complexes and have a major effect on TbTim17 stability. In addition, we found that Tim50 that has a dual-specificity phosphatase activity is involved in an adaptive association with the voltage-dependent anion channel (VDAC) of the mitochondrial outer membrane and plays role in parasite survival during oxidative stress. Based on our preliminary results we hypothesized that TbTims possess unique but critical functions in mitochondrial protein biogenesis as well as participate in the signaling pathway for an adaptive response to cell survival under oxidative stress, which is novel to trypanosomes. We will test this hypothesis by two major aims; 1) determine the unusual and interactive functions of TbTim17, TbTim62 and TbTim50 in T. brucei mitochondrial protein import and 2) elucidate how TbTim50 is involved in the oxidative stress response pathway to maintain cellular homeostasis. We will use many conventional and specialized techniques to evaluate the properties of TbTim17, TbTim62, and TbTim50, including their substrate specificities, ability to assemble the TIM complex, protein-protein interactions, and their essentiality in the bloodstream forms. Using the iTRAQ phosphoproteomic, bioinformatics, and functional genomics analysis we will explore the role of TbTim50 phosphatase on cellular adaptive responses in T. brucei under stress conditions. Together, this knowledge will lay the foundation for developing strategies of an inhibition lethal to the parasite.

Discovery of new anti-amoeba therapeutics

Researcher: Minu Chaudhuri, Ph.D.

Funding source:

National Institute of Allergy and Infectious Disease (NIAID)

R21/R33-subcontract 1R21/R33 AL119782

Project Summary:

Amebiasis and related vision-threatening infections caused by amoebas is a major contributor to diarrheal diseases, primary amoebic meningoencephalitis and cornea problems. Treatment of these infections is challenged by no effective vaccines and limited effective therapeutic options and/or development of resistance. Thus, a need exists for new drugs with more consistent efficacy, less toxicity and exploit the metabolic differences between the parasite and host. Sequencing of amoeba genomes has evoked a broad search for new, pathogen-specific drug targets, of which the sterol C24-methyltransferase (24-SMT) is a clear candidate since it is synthesized in protozoa but not in animals. Notably, 24-SMT is responsible for the introduction of the C1-group into the ergosterol side chain. Although the role of ergosterol and ergosterol biosynthesis enzymes in modulating the infection process from amoeba is poorly understood, our preliminary data of the parasite Trypanosma brucei, whose genome network is similar to the amoeba, revealed that by preventing the biosynthetic renewal of ergosterol augmented protection against infection in a mouse model. In addition, we observed that specific combinations of ergosterol biosynthesis inhibitors were lethal to cell viability. We therefore propose to show ergosterol biosynthesis is required for amoeba cell proliferation and cyst formation, and using one or more agents that selectivity target ergosterol biosynthesis enzymes,24-SMT and sterol 14-demethylase (14-SDM = CYP51), we will show these compounds can produce a disrupted ergosterol homeostasis that thereby, kills cells and provide for better healthcare.

In the R21 phase, we will incubate a series of new mechanism-based inhibitors of ergosterol biosynthesis that differ in the nucleus frame (cycloartenol or obtusifoliol) and electronics of the side chain structure (replace relevant carbon atom with fluorine, sulfur or nitrogen atom) with cultured cells of Acanthamoeba and Naegleria and determine which compounds are the most potent inhibitors of ergosterol biosynthesis, trophozoites growth and cyst formation. Additionally, to make improvements to existing drug therapy we will further evaluate in vitro representative anti-fungal azoles used to treat amoeba infections. These variant inhibitors are designed to inhibit either 24-SMT or 14-SDM action, therefore we will clone [will be performed by our MMC collaborator] and characterize these enzymes kinetically and for product distribution and use them to determine inhibitor specificity, binding and covalent inactivation properties.

The R33 phase will be undertaken with the proof-of-concept demonstrated. We will test in vitro whether our lead molecules that inhibit 24-SMT in combination with traditional chemotherapeutics have synergistic activities. Additionally, in collaboration with Meharry Medical College and UTSoutwestern Medical School, we will evaluate our lead candidate drugs in a mouse model of Acanthamoeba keratitis or primary amebic meningoenchphalitis due to Naegleri fowleri [will be performed by our MMC collaborator]. With the aid of collaborator at Texas Tech University Health Sciences Center, crystal structures of 24-SMT and 14-SDM complexed with relevant inhibitors will be generated to identify binding sites with certainty and should reveal interactions involved with catalysis. ADME/toxicity properties will be evaluated using non-radioactive or 3H-inhibitor fed to healthy mice [will be performed by our MMC collaborator]. Specific steroidal inhibitors determined to possess safe pharmacologic properties would have significant biochemical applications in amoeba chemotherapy.

The overall goal of these studies is to establish mechanism-based inhibitors as a novel class of anti-amoeba agents and to develop therapeutic combinations of drugs (steroidal/ azole inhibitors or these compounds with amphotericin B that target ergosterol biosynthesis and processing to achieve optimal anti-amebiasis effectiveness.

Characterizing a small molecule of Streptococcus cristatus for HIV drug design

Researcher: Bindong Liu, Ph.D.

Funding source: National Institute of General Medical Sciences (NIGMS)

Project Summary: The overall number of people living with HIV-1 has continued to increase in all regions of the world. With no prospect for an effective vaccine, containment of the spread of HIV-1 relies on measures to prevent transmission, and treatment relies on antiretroviral therapy. However, drug resistance is becoming increasingly problematic, with some individuals harboring and transmitting viruses that are resistant to a number of different drugs. Thus, an increasing number of people are left with little or no options for new therapeutics. This highlights the need for the development of new antiretroviral agents. We recently discovered that a small molecule of Streptococcus cristatus CC5A (S. cristatus CC5A) is able to up-regulate APOBEC3G and APOBEC3F expression and inhibit HIV replication. This specific research is aimed to characterize this small molecule and to examine the clinical potential of this small molecule in development of novel anti-HIV drugs. We hypothesize that the small molecule of S. cristatus CC5A enhances innate immunity through up- regulation of APOBEC3G and APOBEC3F expression and could be a potential novel anti-HIV drug candidate. To test the hypothesis, we propose following specific aims. (1) To identify and characterize the small molecule of S. cristatus CC5A that promotes A3Fand A3G expression. (2) To exploit the possibility that S. cristatus upregulates APOBEC3 and inhibits HIV replication or transmission in primary HIV target cells, including CD4+ T-cells, macrophages and dendritic cells. (3) To elucidate the mechanism by which this small molecule activates APOBEC3 gene transcription. The successful completion of this proposal will lay the groundwork for developing the small molecule to a novel anti-HIV drug.

Contribution of cellular factor to HIV-1 assembly

Researcher:Xinhong Dong, Ph.D.

Funding source: National Instituteon Minority Health and Health Disparities (NIMHD)

Project Summary:The global HIV epidemic continues to expand exceeding previous predictions and has become one of the deadliest epidemics in human history. The high prevalence of HIV infection in African-American women points to the need to develop new medical interventions toward eliminating women health disparities in HIV/AIDS. The emergence and transmission of HIV-1 isolates resistant to currently approved drugs makes the discovery of novel anti-HIV drugs with new mechanisms and targets a high research priority. HIV-1 Gag protein directs the highly ordered process of particle assembly and release. Distinct steps involved in these late stages of the HIV-1 replication cycle are being defined, yet significant gaps still need to be filled in our knowledge. By yeast two-hybrid screening of a human cDNA library, we identified a novel Gag-binding partner, filamin A. Filamin A (FLNa) is a non-muscle actin binding protein that plays an important role in cross-linking cortical filaments into a dynamic three-dimensional structure. FLNa interacts with different cellular proteins, and serves as a versatile scaffold required for protein trafficking, signaling transduction, and cell-cell and/or cell-matrix connections. The discovery of the FLNa-Gag interaction in a productive manner in HIV-1 particle assembly and release suggests that FLNa facilitates HIV-1 Gag trafficking to the plasma membrane by regulating the actin cytoskeleton remodeling. The overall goal of this research is to define the molecular basis of the FLNa-Gag interaction and its biological significance. Our studies will provide important new information regarding retrovirus-host interactions, and will impact anti-HIV therapy by discovering and developing novel assembly inhibitors. This research proposal will be accomplished in a series of experiments organized within three integrated specific aims. Specific Aim 1: To define the molecular basis of the FLNa-Gag interaction. Specific Aim 2: To define the mechanism of FLNa-regulated HIV-1 Gag trafficking. Specific Aim 3: To define the role of FLNa in human primary CD4+ T cells and macrophages.

Novel Targets for discovering peptide inhibitors of HIV replication

Researcher: Xinhong Dong, Ph.D.

Funding source: National Institute of Allergy and Infectious Diseases (NIAID)

Project Summary: The continual emergence of HIV strains that are resistant to currently approved anti-HIV drugs is an increasing threat to the effective treatment of HIV infection and control of the HIV/AIDS epidemic. Therefore, the discovery and development of new anti-HIV drugs with novel antiviral mechanisms and targets are urgently needed. The long-term objective of this research is to develop a novel class of anti-HIV drugs representing novel chemical entities targeting late stages of the HIV-1 replication cycle. Our recent studies demonstrate a novel protein- protein interaction between HIV-1 Gag and host filamin A, which is involved in late stages of the HIV-1 replication cycle in a productive manner. Disruption of the interaction redistributes Gag subcellular localization and inhibits particle release. These data suggest that the Gag-filamin A interaction could be developed as targets for HIV therapeutics. We hypothesize that small synthetic peptides, containing the binding site required for the interaction, might block specifically the interaction resulting in the impaired virus assembly and release. Experiments will be performed to test this central hypothesis. In specific aim 1, the binding site for Gag and filamin A will be defined by mutagenesis, as well as in vitro and in vivo binding studies. Surface plasmon resonance (SPR) will be used to evaluate the binding kinetics of the interaction. Experiments in specific aim 2 will be designed to identify peptide candidates to specifically block the interaction. Gag- and filamin A-based libraries with overlapping peptide sequences covering the binding site and its surrounding region will be generated.  Screening for peptide candidates against libraries will be performed using direct binding and competitive binding inhibition assays. The binding dynamics of peptide candidates with target proteins will be characterized. In specific aim 3, the role of peptide candidates on virus assembly and release will be examined. Cellular uptake and targeting validation of peptide candidates, which are mediated by Tat peptide, will be evaluated by fluorescence microscopy and flow cytometry. The role of peptide candidates on HIV-1 assembly and release will be determined in human T cell lines, and primary human CD4+ T cells and macrophages. Taken together, these studies will not only provide new sight into retrovirus-host interaction, but also impact the HIV/AIDS therapy by developing novel peptide inhibitors targeting the Gag-filamin A interaction.

Human brain-on-a chip: Regional communication, drug and toxin responses; and Inner blood-retinal barrier-on-a-chip: Implications for ocular disease

Researcher: Donald J. Alcendor, Ph.D.

Funding source: National Center for Advancing Translational Sciences (NCATS)

Project Summary: Physical or pharmacological disruption of chemical signals between the systemic blood flow and the brain impairs normal functioning and responsiveness of the brain. Long-range chemical signaling through dysregulation of cytokines, nutrients, growth factors, hormones, lipids, neurotransmitters, drugs and their metabolites is also important, but these chemical signals are difficult to quantify and cells are usually studied in isolation. The blood-brain barrier (BBB) dynamically controls exchanges between the brain and body, but this cannot be studied directly in the intact human brain or adequately represented by animal models. Most existing in vitro BBB models do not include neurons and glia with other BBB elements and cannot adequately predict drug efficacy and toxicity. This research will develop an in vitro, three-dimensional, multi-compartment, organotypic model of a central nervous system (CNS) neurovascular unit (NVU) and cerebral spinal fluid (CSF) compartment, both coupled to a realistic blood-surrogate supply system that also incorporates circulating immune cells. Primary and stem-cell-derived human cells will interact with a variety of agents to produce critical chemical communications across the BBB and between brain regions, providing a compact device that faithfully reproduces the properties of the human BBB, the CNS, and the CSF. The proposed in vitro BBB/CNS/CSF model will have a small volume, requires a limited number of human cells, can recreate interactions between different brain regions, and will be coupled in real time to advanced electrochemical and mass spectrometry instruments. This transformative technological platform will replicate chemical communication, molecular trafficking, and inflammation in the brain, and will enable targeted and clinically relevant nutritional and pharmacologic interventions or prevention. This platform will be used to examine the role of the BBB in modulating chemical body-brain interactions, characterize glial and neural cell interactions in the brain, and assess the effect of a wide range of drugs, chemicals, infectious agents and xenobiotics on various brain regions. The model’s clinical utility rests on its ability to 1) recreate unique regions by selecting specific combinations of neurons, endothelial cells, astrocytes, other neuroglia, pericytes and systemic leukocytes, 2) use cells and fluids derived from patients with known pathologies to assess drug treatments and physiological stress from chronic diseases such as obesity and acute injury such as stroke, 3) uncover potential adverse effects during drug discovery as well as those that are being used in clinical trials, such as toxic transformation of approved drugs by brain endothelial cells, 4) detect novel and unbiased correlations between large numbers of chemical signals which converge at the BBB, and 5) combine microfluidic devices, state-of-the-art cell culture and organotypic human brain-cell preparations, analytical instruments, bioinformatics, control theory, and neuroscience drug discovery. An integrated approach will provide technologies of widespread applicability and reveal new mechanistic and region-specific insights into how the brain receives, modifies, and is affected by drugs, neurotropic agents and disease. Dr. Alcendor will aid in integration of vascular pericytes of the neurovascular units (NVU) of the blood brain barrier (BBB) and inner blood retinal barriers (IBRB) to develop separate and unique tri-cell culture models. The model of the IBRB will include retinal pericytes, retinal microvascular endothelial cells and Muller cells.  The BBB model will include brain vascular pericytes, brain microvascular endothelial cells and astrocytes. These tri-cell culture models will be incorporated into a microfluidic device modeled after the normal brain and retina that will allow the monitoring of molecular traffic for therapeutic analysis and cellular responses after CMV infection (diseased brain and retina). Dr. Alcendor will interact with Dr. John P. Wikswo’s team at Vanderbilt and grant collaborators from the Cleveland Clinic in the development of these model devices.

Novel trypanosome receptor for Thrombospondin-1

Researcher: Pius N. Nde, Ph.D.

Funding Source: National Institute of Allergy and Infectious Diseases (NIAID)

Project Summary: Trypanosoma cruzi, the causative agent of Chagas heart disease affects several million individuals causing significant morbidity and mortality, yet it remains incurable. T. cruzi modulates the gene expression profiles of a few extracellular matrix proteins to facilitate infection. One of the genes up-regulated early during infection by the parasite is host thrombospondin-1 (TSP-1), a matricellular protein. TSP-1 binds specifically to the surface of invasive forms of T. cruzi trypomastigotes and knockdown of host TSP-1 by RNA interference causing significant inhibition of T. cruzi infection. We hypothesize that the trypomastigote form of T. cruzi up- regulates host TSP-1 that interacts with trypanosome surface receptor(s) to enhance the infection of heart cells. The long-term goal of this research is to understand the molecular mechanisms that allow T. cruzi to infect heart cells, so that specific molecular intervention strategies can be developed to prevent infection of heart cells. This hypothesis will be tested by experiments based on these specific aims: 1. To clone and characterize the novel T. cruzi TSP-1 binding molecule. We will use affinity chromatography, MALDITOF-MS, PCR and purification of recombinant proteins approaches to identify, clone and characterize the trypomastigote receptor that is important in the process of T. cruzi infection; 2. To determine the in vivo role of TSP-1 gene in the process of T. cruzi infection using TSP-1 KO mice model.

Capacity Building Assistance (CBA) to improve the Delivery and Effectiveness of Human Immunodeficiency Virus (HIV) Prevention Services for High-risk and/or Racial/Ethnic Minority Population

Researcher: Donald J. Alcendor, Ph.D.

Funding source: Center for Disease Control and Prevention (CDC)

Project Summary: The name of this initiative is Project SAVED – Strengthening Access via Empowerment and Diligence. The overall goal of the project is to strengthen the capacity of African American faith leaders, health providers (trained), Historically Black College and University (HBCU) leaders in metropolitan and non-metropolitan US southern states to collaboratively increase access and the use of HIV prevention services for African American high-risk adolescents and adults (predominantly heterosexual) in their communities utilizing the principles of the Centre for Ethnicity and Health Community Engagement Model. Project SAVED will 1) build SCRET’s capacity to utilize the CEH Community Engagement Model to create opportunities for African American high-risk heterosexuals to access and use HIV prevention services, and 2) build SCRET’s capacity to provide trained CBA members who are able to facilitate and empower community stakeholders to be agents of change by identifying and building upon their assets to increase access to HIV prevention and care services. Their roles and responsibilities will be to: 1) provide guidance and input regarding all aspects and activities of the Project SAVED CBA initiative; 2) undergo master trainer education and receive HIV capacity building training regarding the CEH Model, and to in turn diffuse, adapt, and/or adopt the model within their respective communities; 3) mobilize, identify, and engage persons interested in receiving capacity building information and training; and 4) liaison between Project SAVED staff and community stakeholders.

Structural requirements for sterol 14-alpha-demethylases

Funding source:National Institute of General Medical Sciences (NIGMS) R01 subcontract

Researcher: Fernando Villalta, Ph.D.

Project Summary: Sterol 14α-demethylase (CYP51) is a drug target in lower eukaryotic pathogens such as Trypanosoma cruzi, which causes Chagas disease, because the reaction it catalyzes is essential for membrane formation and therefore loss of this activity is lethal. There are no effective treatments for Chagas disease, which causes significant mortality worldwide and represents a serious global health problem. In this project, in collaboration with Dr. Galina Lepesheva at Vanderbilt University, the team focuses on structure-based development of selective inhibitors for protozoan CYP51s.  They also will synthesize derivatives of the three original scaffolds they discovered that bind to the active site of the enzyme and analyze the efficacy of the best of these derivatives in disease models. The results arising from these studies will lead to rational design of pathogen-selective drugs for the treatment of Chagas disease.

Molecular microbial pathogenesis training program

Researcher:Fernando Villalta, Ph.D.

Funding Source:National Institute of Allergy and Infectious Diseases (NIAID)

Project Summary:   Highly interactive Meharry Medical College and Vanderbilt University mentors who conduct cutting-edge research in molecular microbial pathogenesis participate in this training. The program, for trainees committed to infectious diseases careers, offers trainees opportunities for new discoveries and breakthroughs in the study of the pathogen-host interactions of microbes causing disease including biodefense agents. The innovative features of this program are grounded on cutting-edge science and molecular approaches to study the pathogenesis of microbe-host cell interactions in the following areas: (i) Microbial attachment to receptors, invasion and replication; (ii) Functional genomics and systems biology of microbial infections; (iii) Cell host signaling evoked by pathogens including toxins; (iv) Unique pathogen target genes required for survival; (v) Structural biology and function of new microbial virulent factors; and (vi) Interactions of novel immune molecules with pathogens.

Research training in cardiovascular biology at Meharry

Researcher: Fernando Villalta, Ph.D.

Funding Source: National Heart, Lung and Blood Institute (NHLBI)

Project Summary: This is the third renewal of a NHLBI-supported Minority Institutional Research Training Program in cardiovascular biology at Meharry Medical College (MMC) that will focus in the considerable strengths and diversity of multidepartmental research in cardiovascular biology at MMC and Vanderbilt University School of Medicine (VUMC) into a unique and coherent framework for specialized training. The proposed program will support five pre-doctoral trainees per year and will involve 28 faculty members at MMC and VUMC. Three departments including Cardiovascular Biology at MMC and six departments at VUMC, participate in the program. The research training will focus in cardiovascular biology using cutting edge science and approaches to elucidate mechanisms causing cardiovascular as well as hematologic diseases.

Research Centers in Minority Institutions (RCMI)- Molecular Biology Core Component

Researcher: Robert Holt, Ph.D.

Funding Source: National Institute on Minority Health and Health Disparities (NIMHD)

Project Summary: Dr. Holt is the Scientific Director of the Molecular Biology Core at Meharry Medical College supported by RCMI. This core is a multi-functional facility that provides to faculty, students and staff of the college the primary service of DNA sequencing but also provides access to shared equipment housed in a centralized location and facilitates convenient and rapid access to frequently used molecular biological reagents. This core supports the enhancement of the research enterprise at the College.

Molecular analysis of trypanosome infection

Researcher: Fernando Villalta, Ph.D.

Funding source: National Institute of Allergy and Infectious Diseases  (NIAID)

Project Summary:  Dr. Villalta’s laboratory studies the molecular interface between the human protozoan Trypanosoma cruzi and its host, including the host and pathogen molecules required for intracellular parasitism, mechanisms of pathogenesis and strategies for control. These studies combine a genetics system approach with protein structural analysis, knockout and transgenic animal and parasite models, electron, video and confocal microscopy, functional genomics, gene network analysis and bioinformatics in acute and chronic models of disease.  This research program is aimed to discover the cellular and molecular basis of host cell invasion by T. cruzi and identify the molecular signatures caused by the parasitein host cells leading to pathogenesis and disease. Fundamental questions about the structural basis of molecular interactions involved in the pathogenesis of Chagas disease are being addressed. This work will provide clues to the structure and function of the key virulence factors that are implicated in gastrointestinal and cardiac pathology of Chagas heart disease.

Mechanism based targeted therapies for membranous nephropathy

Researcher: Dorin Bogdan Borza, Ph.D.

Funding Source: Satellite HealthCare, Inc.

Project Summary: Membranous nephropathy (MN) is a major cause of nephrotic syndrome in adults. Up to 40 percent of patients progress to end-stage kidney disease, and another 30 percent suffer from complications of persistent proteinuria and chronic kidney disease. Current therapies are unsatisfactory. Development of much-needed novel therapies require a better understanding of the pathogenic mechanisms. This study will test the hypothesis that the formation of subepithelial immune complexes promoting complement activation via the alternative pathway plays a central role in the pathogenesis of membranous nephropathy, mediating damage to the glomerular filtration barrier and proteinuria. It aims to determine whether targeted therapies specifically inhibiting the activation of the terminal complement cascade or of the alternative pathway , as well as the ablation of plasma cells producing pathogenic antibodies, are effective strategies for ameliorating glomerular damage and proteinuria in animal models of MN. The new knowledge gained from these studies may eventually translate into new treatments for human disease.

Mitochondrial inner membrane protein translocase in trypanosoma brucei

Researcher:Minu Chaudhuri, Ph.D.

Funding Source: National Institute of General Medical Sciences (NIGMS)

Project Summary: African trypanosomiasis, a fatal disease in humans as well as in domestic animals, is caused by the parasitic protozoa, Trypanosoma brucei. As available drugs for this disease are inadequate, it is critical to identify targets to design new drugs. Import of essential mitochondrial proteins is crucial for survival of this parasite in mammalian hosts. Therefore the unique structure and function of mitochondrial protein import molecules could be exploited as novel drug target(s).

Mechanism of biogenesis of atypical alphaviruses

Researcher: Raju Ramasamy, Ph.D.

Funding Source: National Institute of Allergy/Infectious Diseases (NIAID)

Project Summary: Dr. Raju’s long-term goal is to elucidate the pathways of alphavirus RNA genome repair and remodeling leading to the generation of atypical viruses in infected host cells. Alphaviruses are an important cause of emerging viral encephalitides in animals and humans and are significant biodefense agents. Delineating these pathways should lead to strategies to control emergence of outbreaks of alphaviruses and perhaps other mosquito-transmitted RNA viruses. Since alphaviruses are vigorously pursued as gene therapeutic and vaccine delivery vehicles, the team’s work will also be useful in the development of improved RNA vectors.

Control of nociception in the spinal cord (Neurobiology of Pain and Analgesia: Sex-Related Differences)

Researcher: Sukhbir S. Mokha, Ph.D.

Funding Source: National Institute of General Medical Sciences (NIGMS)

Project Summary: Many pain syndromes / disorders such as migraine, trigeminal neuralgia, and irritable bowel syndromes have a higher prevalence in women as compared to men. The goal of our research is to understand the underlying biological mechanisms that make women more vulnerable to the development of pain syndromes and enhance our understanding of the sex-related differences in the regulation of pain throughout the life span. Our research is specifically focused on the genomic and non-genomic effects of sex steroid hormones on the regulation of pain by G protein coupled receptors such as the opioid receptors. Our research will lead to the development of new and better therapeutic strategies for the treatment of pain.

Sleep Disturbance and Adverse Pregnancy Outcomes

Researcher: Sanika Chirwa, Ph.D.

Funding Source: Eunice Kennedy Shriver National Institute of Child Health and Human Development (pending)

Project Summary: The goal of the study is to understand the causal links between poor sleep profiles (i.e. chronic sleep debt, disturbances, and quality) in pregnant women and occurrence of adverse outcomes – e.g. preeclampsia, gestational diabetes, hemorrhage, intra-uterine growth restriction, preterm delivery and macrosomia. We are testing two inter-related hypotheses namely: 1) Sleep disturbance is a potent stressor that independently triggers the release of cortisol. Unbalanced cortisol release, in turn, fosters metabolic abnormalities leading to adverse pregnancy outcomes; and 2) Sleep disturbance will independently attenuate insulin sensitivity, and, thereby, cause impaired glucose tolerance resulting in metabolic abnormalities. The concept that severe sleep disturbance is a potent stressor with the capacity to unbalance the intricate catabolic states that occur in the second half of pregnancy and result in adverse outcomes is innovative. If verified, this will help guide the development of evidence-based screening test(s) for early detection and curtailment of adverse pregnancy outcomes.

Educational and research interventions for the nuclear regulatory commission

Researcher: Clivel Charlton, Ph.D.

Funding Source: Nuclear Regulatory Commission

Project Summary: The ultimate goal of activities conducted under this activity seek to establish scientific research programs with Y12 National Security Complex scientists to better understand the consequences of nuclear fallout disposition to the developing central nervous system and subsequent effects on cognitive processes in vulnerable military populations. Activities under this award will also serve to provide a customized pipeline for minority biomedical scientist and occupational and environmental medicine positions at Y12, Oak Ridge National Laboratory and other national security complexes.

In Utero Exposure to Methamphetamine: Risks and Adverse Outcomes in Progeny

Researcher: Sanika Chirwa, Ph.D.

Funding Source: National Institute of Drug Abuse (pending)

Project Summary: The goal of this project is to understand in detail the risks and attendant cognitive-behavioral dysfunctions in off-springs exposed to methamphetamine in utero. The project entails using behavior tests for episodic memory (i.e. novel object recognition) coupled with in vivo electrophysiological recordings for studying synaptic plasticity and neural network interactions in the hippocampus, a brain structure that is critical for episodic memory acquisition and consolidation. Data from this project will help clarify how and by what mechanisms exposure to methamphetamine in utero subsequently affects mnemonic functions in off-springs.

Sex-based and individual-based differences in the comorbidity of drug addiction and mood disorders.

Researcher: Akiko Shimamoto, Ph.D.

Funding Source: Research Centers in Minority Institutions (RCMI)

Project Summary: This project investigates molecular, neuronal, and behavioral mechanisms underlying chronic stress-induced addictive behaviors in both males and females. The main focus of this project is brain reward pathway, including dopamine, glutamate, and GABA neurons. The proposed research will help us understand how drug addiction is influenced by mood disorders such as depression, and will lead to a more effective treatment for these individuals.