Signaling transduction of lipoprotein receptors in the arterial wall

Erwin Schrödinger Fellowship J 1950 Signaling of lipoprotein receptors in the arterial wall Peter MARSCHANG 09.10.2000 Different cells of the arterial wall (endothelial ceUs, monocyte derived macrophages, smooth muscle cells) play a major role in the pathogenesis of atherosclerosis. A number of different lipoprotein receptors are expressed on the surface of-these cells, including members of the LDL receptor family (LDL receptor, LRP, VLDL receptor) which share a common structure including a variable number of ligand binding domains, an EGF precursor domain and a cytoplasmatic tail with NPxY motifs. These lipoprotein receptors have been found in normal arteries as welt as in atherosclerotic lesions, where the expression of some these receptors is markedly increased. Recently, two members of the LDL receptor family have been identified to be integral components of the Reelin signaling pathway and to bind to intracellular adaptor proteins in neuronal cells. The objective of the research proposal is to study the signal transduction of lipoprotein receptors in the arterial wall. Candidate intracellular proteins binding to the cytoplasmatic tails of lipoprotein receptors will be identified by the screening of DNA libraries. The expression of identified adaptor proteins and non receptor tyrosin kinases will be investigated by immunohistochemistry and in situ hybridisation. The functional role of the signaling pathways will then be tested using in vitro cell culture models and in vivo models of knockout mice lacking lipoprotein receptors. These studies may provide insight into the regulation of cellular events in the pathogenesis of atherosclerosis, as eg. adhesion molecule expression by endothelial cells, proliferation of smooth muscle cells and the release of proteinases by macrophages. Signals mediated by lipoprotein receptors in the arterial wall may have an important impact on the fate of atherosclerotic plaques by triggering cellular responses leading to plaque stabilisation (e.g. fibrous cap formation) or plaque rupture. (e.g. secretion of proteases).