Protein, and lipid-derived Advanced Glycoxidation Endproducts (AGE) have been linked to a spectrum of cellular oxidative responses leading to tissue injury via enhanced cytokine, growth factor, matrix production, vascular dysfunction, and atherogenesis. Vascular endothelial cells (EC) and other cells express a spectrum of AGE-binding proteins, some of which mediate endocytosis and clearance, but others trigger oxidant stress via ROS generation, and Nf-kB activation, contributing to inflammatory events, in a self perpetuating manner, which in the presence of diabetes, leads to accelerated atherogenesis. Based on presented evidence, we propose that in diabetes and/or aging normal AGE detoxification mechanisms are overwhelmed by marked increases in AGE burden, from exogenous and endogenous sources, and the resulting glycoxidant excess, together with other metabolites (glucose, lipids) leads to low-grade inflammatory state, underlying diabetes and diabetic vascular injury. The main goal of this Continuation proposal is to identify possible mechanisms by which environmental oxidant or carbonyl stress and systemic vascular toxicity can be balanced, either by enhancing AGE-receptor (AGER) mediated clearance or by inhibiting AGE-promoted inflammatory signaling cascades. This goal will be approached by assessing:
Aim 1 a: Early AGER signaling events of endocytotic pathways vs. Nf-kB activation pathways and of AGER-dependent negative or inhibitory cell activation pathways in endothelial cells or macrophages (Mf) over-expressing AGER1, R2, R3 and RAGE; 1b. Differences in AGER signaling in cells from aging mice, Aim 2a. Effects of environmental AGE stress on AGE-R clearance vs activation as a function of age in mice: in vitro studies, or 2b., in ApoE-deficient mice, a model of atherogenesis.
Aim 3 a: Effects of AGE-binding peptide, Lysozyme peptide (LZ-p) overexpression on AGER signaling, and 3b: In vivo effects of Lz-p on AGER-mediated clearance and tissue pathology in Lz-p transgenic mice, exposed to high AGE states, eg. diabetes, diet. The proposed studies will expand our understanding of this basic process and may allow us to identify ways to prevent AGE-induced vascular injury due to diabetes and aging.
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