Proteomic Analysis of Apoptotic Signaling Networks

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DESCRIPTION (provided by applicant): Apoptosis is a physiological cell death mechanism that has been shown to be involved in physiological and pathological events in man. Deregulation of apoptosis has been implicated in pathogenesis of human coronary artery disease, vascular remodeling, and vascular inflammation. We have investigated molecular biology of vascular cell apoptosis and made two significant contributions; we have discovered that massive apoptotic responsive in vascular smooth muscle cells invoke profound inflammatory response in the vessel wall, and apoptotic cells in general including the vascular smooth muscle cells utilize a novel endogenous engulfment ligand receptor system to facilitate engulfment of apoptotic cells. The discovery of the first endogenous protein ligand, annexin I, and its receptor, the phosphatidylserine receptor (PSR), was achieved by the use of high-throughput proteomic profiling technology, termed the 3-Dimensional Isotope-Coded Affinity Tags and mass spectrometry. Although significant progress has been made in the identification of a crucial ligand: receptor pair that controls apoptotic cell engulfment in the vascular cells, comprehensive understanding of signaling mechanisms associated with how apoptotic cells are recognized and internalized is lacking. The long-term objectives of this competitive renewal application is to study the molecular biology and associated functions of PSR, its control mechanisms, its interacting protein complexes, and the function properties of PSR associating proteins. We will utilize proteomics technologies that are established in the laboratory together with traditional biochemical, immunological, imaging, tissue culture models of vascular cells, and genetics model system. Specifically, we will study the basic mechanisms of PSR mediated apoptotic cell recognition, PSR mediated signaling events, interactions of PSR and other receptors in response to apoptotic cells and to chemo-attractants secreted by the apoptotic cells, signaling-dependent interactions of PSR and cytosolic signaling molecules, and elucidate the mechanisms of how PSR mediates the overall apoptotic cell engulfment. The proposed studies are anticipated to provide novel insights into the molecular biology of how apoptotic cells are recognized and cleared in the vessel wall to prevent vascular inflammation.