Pilot Project #1 - Identification of Molecular Targets for African American Prostate Cancer Patients Using miRNA Profiling
Principal Investigator - Clayton Yates, PhD, Assistant Professor, Biology Department
Although concerted efforts have been directed towards eradicating prostate cancer health disparity in theUnited States, African American men still have the highest incidence and mortality rate in the world. Whereas it is probable that causative factors involved in the progression of this disease are multifactorial, experimental models that can give us a better understanding of molecular determinants associated with the aggressiveness of this cancer are invaluable. Recently we reported that expression levels of two metastatic markers of invasive cancers, increased expression of epidermal growth factor receptor and decreased expression of the cell adhesion molecule, E-cadherin, are reversed when prostate cancer cells are colonized with the liver microenvironment. These findings suggest epigenetic regulation of genes occurs throughout cancer progression. MicroRNAs (miRNAs), small non-coding RNAs. are regulators of many of the events involved in cancer invasion and metastasis. Differences in the miRNA expression in normal prostate tissues from African American and Caucasian men highlight the possibility that similar miRNA differences may also exist in their prostate cancer counterparts. Therefore the overall objective of this proposal is to test the hypothesis that differential expression of miRNA in African American versus Caucasian males contribute to the epigenetic regulation of gene expression throughout prostate cancer progression, and that this regulation is influenced by the tumor microenvironment. We propose the following specific aims: 1) Identify and compare cancer-specific miRNA signatures of African American and Caucasian prostate cancer patients. 2) Determine the influence of the prostatic tumor microenvironment on the miRNA profiles of African American and Caucasian prostate cancer cells. 3) Utilize 3-D co-culture models to determine the role of metastatic tumor microenvironment on the molecular regulation of miRNA expression in African American and Caucasian prostate cancer cells. The completion of these investigations will delineate important questions at the core of the cancer health disparity issue, such as differences seen in tumor time of progression, volume, invasiveness and occurrence.
Pilot Project #2 - Community Based Epidemiologic Research to Address HIV/AIDS in the BBC of Alabama
Principal Investigator - Berhanu Tameru, PhD, Associate Professor and Director of CCEBRA and BIMS, CVMNAH
This project focuses upon translational, participatory, community based, computational epidemiologic researchwith an emphasis on a health disparity disease of major concern, that of HIV/AIDS. Of all racial and ethnicgroups in the US, HIV/AIDS has hit African-American (AA) the hardest. Even though AA make up only 13% ofthe US population, half of the estimated new HIV/AIDS diagnoses in the US in 2005 were among AA. The goalis to use computational epidemiologic methods and concepts to provide the framework for addressing healthdisparities in a multidisciplinary and integrative manner with a focus upon HIV/AIDS scourge that is devastatingAA communities including the Black Belt Counties (BBC) of Alabama. The specific aims are to: 1) Developa static, multivariate epidemiologic model that integrates multiple determinants (biomedical, behavioral, andsocioeconomic factors) targeted to address HIV/AIDS in AA within the BBC. Develop a dynamic systemsanalysis model for aim 1 enabling us to determine (a) if drug therapy impacts HIV/AIDS progression rates andincidence rates in the BBC; (b) how behavior modification reduces HIV transmission and HIV/AIDS progressionrates, and (c) how socio-economic factors impact HIV transmission and progression rates. 3) Develop decisionmaking health index models based on methodologies of risk analysis that can be used to assess if there isa significant reduction of the HIV/AIDS health disparity burden in the BBC and to assist in selecting effectivetherapeutic, preventive and control alternatives.4) Use results from the developed integrated epidemiologicmodels, complemented by multimedia and scientific visualization resources, in education and outreach topromote effective HIV/AIDS control and prevention practices and reduction of risk factors. The hypothesesare formulated based on our previous research findings as well as preliminary data collected in collaborationwith the Montgomery Aids Outreach (MAO), Inc. and through several community based meetings that wereconducted with community representatives, who suggested some of the key factors associated to the highrisk behaviors in the BBC. Using these computational epidemiologic models as the experimental medium,various intervention scenarios will be evaluated to recommend effective strategies in minimizing the risk ofnew infections and to manage existing infections in the BBC. In the long run, it is these types of targetedapproaches that could reduce the disparity in health and disease in the BBC and other counties in Alabama.
Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women of all ethnicand socioeconomic groups in the United States. Higher morbidity and mortality rates are observed amongwomen of African descent than among Caucasian women. SLE is characterized by aberrant responsesof the immune system to self-antigens that result in injury to tissues such as the skin, joints and kidneys.Several mechanisms have been proposed for the development of SLE including deregulations of centraltolerance in the thymus. During this process developing T cells (thymocytes) are restricted to self MHCby epithelial cells of the thymic cortex. The process requires that intimate contacts are continually madebetween thymic epithelial cells and thymocytes. Changes in the composition of thymic epithelia wouldtherefore negatively impact thymocyte education and the development of self tolerance. A common defectnoted in the thymic epithelia of all SLE mice models is a severe reduction in thymic nurse cells (TNCs). TNCsharbor αβTCRloCD4+CD8+ (triple positive) thymocytes and macrophages within cytoplasmic vacuoles.Observed interactions between these cells suggest that TNCs provide a microenvironment for the selectionof triple positive thymocytes. TNC depletion in SLE mice coincides with a number of changes in the thymicenvironment. These include the appearance of epithelial free zones in the thymic cortex, a decrease inapoptosis among triple positive thymocytes known to undergo MHC restriction in the thymus and decreasedlevels of IL-12 production. The goal of this study is to examine the contribution of the TNC microenvironmentin the pathogenesis of SLE. We propose to: 1) transfer TNCs from normal animals into the thymi of syngenicpre-diseased lupus-prone mice. Animals will be followed to determine if normal epithelial morphology isreestablished and disease is prevented. 2) Use in vitro systems to analyze the contributions of macrophagesin the TNC microenvironment in the selection of triple positive thymocytes. 3) Analyze the requirement of IL-12for TNC-mediated selection of triple-positive thymocytes.