423 Sanders Brown Center on Aging Academic Appointments: • Department of Pediatric, College of Medicine Education: • B.S., Department of Biochemistry, University of Maine-Orono Awards: • Irvine H. Page Young Investigator Award Specific Interest in Nutrition: Diets Induced Diabetes Research: Our laboratory takes a vertically integrated approach to mechanistically study important and interrelated cardiovascular diseases, namely atherosclerosis, hypertension, and diabetes. These three cardiovascular diseases are tightly correlated and together account for the vast majority of deaths in Western societies. These diseases are multifactorial, that is, many genetic and environmental factors directly influence the manifestation of each pathophysiology. In addition, these diseases are the result of changes in both lipid metabolism and protein-mediated signal transduction. Studies involving lipids and proteins have historically been done in isolation from each other; however, we have made significant progress in dissecting signaling mechanisms common to numerous cardiovascular diseases by combining the strengths of both fields. Similarly, our laboratory uses biochemistry, cell biology and whole animal physiology in a concerted effort to understand the signaling pathways involved in controlling physiological parameters. The thread that binds our research program together is plasma membrane microdomains called caveolae or lipid rafts. The concept of caveolae/lipid rafts is simple but has far-reaching biological implications. Basically, a caveola is a site on the cell surface that provides a place for proteins and lipids to interact and generate signals in a highly regulated and specific manner. The goal of Project 1 is to determine the mechanisms responsible for trafficking cholesterol between the endoplasmic reticulum and caveolae. We have discovered a novel mechanism for intracellular cholesterol transport. We are currently studying how this transport mechanism controls the generation, structure, and function of caveolae. Aberrant regulation of this basic process can lead to dramatic alterations in cellular lipid composition, signaling pathways, and ultimately cell death. The goal of Project 2 is to determine the role of caveolae, scavenger receptors, lipoproteins, and nitric oxide synthase in the generation of hypertension. This project is divided into two approaches. In the first approach, we are using human endothelial cell lines to dissect the signaling pathways that may be involved in generating nitric oxide, a potent vasodilator. In the second approach, we are using mouse models that have the relevant genes knocked-out, that is, the corresponding proteins are not expressed. We use these animal models to measure blood pressure, flow, and peripheral resistance. We have demonstrated that oxidized LDL disrupts caveolae structure thereby causing the mis-localization of nitric oxide synthase and a decrease in the generation of nitric oxide, which promotes hypertension. More recently we have demonstrated that estradiol associated with HDL can stimulate nitric oxide generation which may explain in part the cardioprotective effects of HDL in women. Future studies are focusing on how the lipid signaling pathways interact with the protein signaling pathways and lead to the pathophysiology of cardiovascular disease. The goal of Project 3 is to study the role of caveolae, caveolin, and SR-BI in macrophage foam cell formation. Macrophage foam cells are central to the development of atherosclerotic lesions. Again we have a dual approach where we develop and test specific molecular mechanisms in macrophage cell lines. We have demonstrated that in macrophage cells caveolae act as “gate keepers” for the uptake and efflux of cellular cholesterol. The accumulation of cholesterol in macrophage cells induces the generation of foam cells and atherosclerotic lesion development, however, the protein machinery and signaling pathways involved in this process are not understood. We are also creating transgenic mice that overexpress SR-BI and caveolin in a macrophage-specific manner. The expression of these proteins on atherosclerotic lesion formation and the relevant signaling pathways will then be determined. The goal of Project 4 is to study how HIV infection “takes over” the signaling functions of caveolae/lipid rafts and promotes the generation of more infectious particles. This complicated process involves numerous signaling systems such as src kinases, molecular chaperones, and chemokine receptors. Interestingly, the lipid composition of caveolae/lipid rafts appears to be directly involved in the ability of the viral particles to interact with the cells. 5. Xiang-An Li, William V. Everson, and Eric J. Smart (2005) Caveolae, Lipid Rafts and Vascular Disease. Trends in Cardiovascular Medicine 15 (3): 92-96. 6. Zhu, W, Smart, EJ (2005) Myristic acid stimulates endothelial nitric oxide synthase in a CD36 and an AMP kinase-dependent manner. J Biol Chem. 280 (33): 29543-29550.
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