(provided by candidate): Dr. Jennifer Yearley graduated with her DVM degree from Washington State University College of Veterinary Medicine in 2001, and completed training in veterinary anatomic pathology at the NEPRC in July of 2006. She was involved with studies of bacterial pathogenesis while in veterinary school, and has been working in animal models of lentiviral pathogenesis and AIDS since 2002. Dr. Yearley's research at the NEPRC has centered on the pathogenesis of cardiomyopathy in the context of SIV/HIV infection, and this work forms the basis of her present doctoral studies. Dr. Yearley ultimately intends an academic research career examining the role of inflammation in cardiovascular disease. Cardiomyopathy occurs at much higher rates among HIV-infected people than in the general population and preliminary studies conducted at the NEPRC using the SIV-model of HIV infection, have implicated exaggerated Myocardial inflammatory cytokine responsiveness to stimulation with ubiquitous agents known to engage toll-like receptor 2 (TLR2) as important contributory factors to development of cardiac dysfunction. Based on these findings, we hypothesize that HIV-infected individuals show increased TLR2 expression and/or amplified TLR2-mediated signal transduction on myocardial cell populations, with resulting enhancement of cardiac inflammatory cytokine responses and subsequent ventricular dysfunction, pathological structural remodeling, and ultimately heart failure. To address the predictions made by this hypothesis, in our first aim we will subject SIV-infected rhesus monkeys to long-term, systemic stimulation with heat-inactivated Mycobacterium avium, assessing myocardial TNFalpha, IL-1beta, and IL-18 mRNA and protein levels, and correlating systemic and myocardial cytokine levels with the development and progression of cardiac dysfunction and remodeling. In our second aim, we will characterize the relationship between levels of TLR2 expression and systemic and myocardial inflammatory cytokine production in response to TLR2 stimulation in the context of SIV infection. In our third aim, we will characterize differences in inflammatory signal transduction pathway activation in SIV/HIV infection in response to TLR2 ligation. The NEPRC is an outstanding environment for research training, with superb facilities, unique resources, and world-class researchers, providing a rigorous context for pursuit of scientific investigation. ? ? ?
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