PROJECT SUMMARY/ABSTRACT On a daily basis, we turnover billions of apoptotic cells that are removed by phagocytic cells, such as macrophages. The processes of cell death and phagocytic clearance are vital to maintaining homeostasis and are related to many disease pathologies. As atherosclerotic plaques develop, monocyte-derived macrophages infiltrate vessel walls to remove cholesterol-rich lipoproteins and cellular debris, but these lipid-laden macrophages eventually become impaired in their phagocytic activity and undergo apoptosis (a form of cell death) due to prolonged exposure to inflammatory stimuli. Uncleared apoptotic cells eventually progress to secondary necrosis, and as their plasma membranes become permeabilized, intracellular contents are released into the surrounding microenvironment, further stimulating an inflammatory response. Advanced atherosclerotic plaques with large, inflammatory necrotic cores develop as uncleared dead cells and debris accumulate within vessel walls. Thus, modalities are needed to enhance the clearance of dead cells and promote inflammation resolution within advanced plaques. In addition to professional phagocytes (such as macrophages, which are impaired in atherosclerotic lesions), non-professional phagocytes also exist and participate in the clearance process, such as epithelial cells in the digestive tract and lung, or mesenchymal cells during embryonic limb development. These non-professional phagocytes can play vital roles in maintaining homeostasis, yet the potential of non-professional phagocytes to help in the clearance of atherosclerotic plaques has not been addressed. Based on our preliminary studies, loss of the tyrosine phosphatase, SHP-2, enhances the clearance of apoptotic cells by non-professional phagocytes such as fibroblasts in vitro. We propose to further test the role of SHP-2 as a novel brake on the clearance of dead cells, and define the mechanism(s) and immunologic responses underlying this phenotype. Further, we propose to test the role of SHP-2 in modulating atherosclerotic plaque clearance in vivo. Understanding the role of SHP-2 in regulating the phagocytic process by different types of phagocytes at homeostasis and in atherosclerotic plaques will provide important therapeutic opportunities for atherosclerosis.

PROJECT NARRATIVE Cardiovascular and cerebrovascular diseases are a leading cause of death in the United States, and atherosclerosis is a major contributing factor in the pathogenesis of these diseases. Cell death is a key process in atherosclerosis pathology and impaired clearance of these dying cells promotes plaque progression and instability, thus leading to heart attack and/or stroke. This proposal aims to study the role of the tyrosine phosphatase, SHP-2, as a novel brake on dead cell clearance, with the goal of manipulating SHP-2 function in phagocytes to enhance dead cell clearance and promote atherosclerotic plaque regression.