DESCRIPTION (provided by applicant): Atherosclerosis and its complications are the leading cause of deaths worldwide. They also significantly contribute to the health care financial burden and are the major leading causes of mortality and morbidity in the United States. Clinical, pathological and experimental studies support an important role for macrophages in the development and progression of atherosclerotic lesions. A hallmark event in the development of atherosclerotic plaque is the accumulation of lipid-laden macrophage derived foam cells in the sub endothelial layers of affected blood vessels. Despite its public health importance, the molecular events that govern macrophage activation and its contribution to the pathogenesis of atherosclerosis are not well understood. We have recently identified KLF6 as a critical transcriptional regulator of macrophage inflammatory gene expression and function. Our observations indicated that, (1) KLF6 is the most abundantly expressed Kruppel-like transcription factor in macrophages; (2) KLF6 expression is elevated in macrophages following exposure to pro-inflammatory stimuli such as IFN-γ and oxLDL; (3) KLF6 promotes pro-inflammatory gene expression in macrophages; (4) treatment with anti-inflammatory cytokines suppress macrophage KLF6 expression; (5) KLF6 expression is elevated in macrophages derived from human atherosclerotic lesions; (6) Myeloid deficiency of KLF6 attenuated macrophage lipid influx gene expression, lipid accumulation and foam cell formation. Based on these observations, we hypothesize that KLF6 is a critical regulator of macrophage pro-inflammatory activation, lipid homeostasis, foam cell formation and atherogenesis. We propose following aims to determine the precise role of macrophage KLF6 in pathogenesis of atherosclerosis. In Aim 1, we will examine the precise molecular mechanism by KLF6 regulate inflammatory gene expression. In Aim 2, we will determine the role of KLF6 in macrophage lipid homeostasis and foam cell formation. In Aim 3, we will investigate the role of myeloid KLF6 in experimental models of atherosclerosis. At the conclusion of these studies, we will have expanded our knowledge of myeloid KLF6 contribution to the pathogenesis of atherosclerosis. This may provide the molecular insight to design novel therapies directed at the treatment of atherosclerosis.

PUBLIC HEALTH RELEVANCE: Atherosclerosis and its complications are the leading cause of deaths worldwide. In addition to this, they also significantly contribute to the health care financal burden and are the leading causes of mortality and morbidity in the United States. Macrophages are an essential component of the innate immune system and contribute to the pathogenesis of atherosclerosis through accumulation of cholesterol and production of inflammatory cytokines and chemokines. This project investigates the role of KLF6 in macrophage inflammatory gene expression, lipid homeostasis, foam cell formation and atherogenesis. The results of our studies will provide the molecular insight to design novel therapies directed at the treatment of atherosclerosis.