Program Project: The Atherogenic Microenvironment

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DESCRIPTION (provided by applicant): Cellular processes related to the initiation and progression of the atherosclerotic lesion remain incompletely defined. The integrated, unifying theme of this new PPG is to define how the atherogenic micro- environment of the vessel wall aberrantly recruits and modifies the function of hematopoietic and vascular cells leading ultimately to the complex atheromatous plaque. By studying the role of blood borne cells in atherogenesis and their subsequent cellular and chemical modification, all five project leaders will attempt to decipher those signals that trigger plaque formation. This PPG is based on the hypothesis that atherogenic lipids and growth factors modify cellular recruitment and promote smooth muscle cell and macrophage-derived foam cell formation. Project 1 will define the physiological role of scavenger receptors (e.g. CD36) in the uptake and metabolism of oxidized LDL, focusing on the mechanisms by which lipid accumulation impacts cholesterol uptake and efflux in lesional cells. We will also determine the impact on these receptors in regulating fatty acid metabolism and insulin resistance on atherosclerotic lesion development. Project 2 will assess the effects of cholesterol modulation and lipoprotein interactions on monocyte/macrophage functions such as migration. In Project 3, we will assess mechanistically how lipids and cytokines of the atherogenic environment affect the differentiation, trafficking, and fate of monocytes favoring differentiation into foam cells and their retention in the lesion. Since the Cornell group has demonstrated that growth factors associated with the nervous system and bone marrow can also contribute to atherosclerotic lesion development and tissue remodeling, Project 4 is crafted specifically to define how cell progenitors responsive to angiogenic growth factors (e.g. VEGF) can promote atherogenesis when recruited into arteries. In Project 5, the role of proteolytic cleavage of growth factors modulating cell recruitment and apoptosis in the developing atheroma will be defined as well as processes related to lesion remodeling. Each project specifically builds on many of the concepts conceived by the other projects in this Program. The Cores are designed to assist in administrative functions of the PPG and to provide and centralize those services necessary to perform the planned histological and immunohistochemical experiments. In addition, electron microscopic/image analyses will be performed on the atherosclerotic tissue and co-cultures as outlined in many of the projects. It is anticipated that our experimental results will advance our knowledge base of the cellular factors that are responsible for the progression of the human atheromatous lesion.