This application is designed to develop the principle investigator to become an independent physician scientist. To accomplish this goal the PI proposes a detailed program involving the dissection of several important molecular signaling pathways in macrophages. Dr. Alan Aderem, a leader in the field of macrophage biology and signaling, will mentor the PI through this program. The training program also includes specific course work, attendance at seminars, and the formation of a scientific advisory committee. The purpose of this proposal is to analyze the effect of the HMG-CoA reductase inhibitor simvastatin on the immune function of macrophages. Atherosclerosis is a chronic inflammatory disease and macrophages play a central role in all phases on the process including initiation, progression and the eventual acute complications. Macrophages coordinate the innate and specific immune system through their ability to phagocytose and clear pathogens and couple this to the release of inflammatory mediators. The HMG-CoA reductase inhibitors, or statins, are a class of drug designed to inhibit cholesterol synthesis that have been shown to dramatically reduce cardiovascular disease endpoints. However, their lipid lowering properties incompletely explain the beneficial effect of these drugs.
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