"The Role of Signaling Adaptor Protein Epsin in Atherosclerosis"

描述（由申请人提供）：被困在内皮下层的LDL氧化引发的动脉炎症反应是驱动动脉粥样硬化斑块发生、进展甚至破裂的关键过程。然而，由于缺乏适当的靶点，目前还没有有效的药物或治疗方法来破坏炎症过程。ep蛋白酶是一组结合网格蛋白并参与网格蛋白包被囊泡内吞作用的蛋白质。我们的研究表明内皮细胞表达的epsin在动脉粥样硬化的发病机制中起重要作用。epsin的缺失

DESCRIPTION (provided by applicant): The arterial inflammatory responses initiated by the oxidation of LDL trapped in the subendothelium are a key process that drives the initiation, progression, and even rupture of atherosclerotic plaques. However, there have been no effective medicines or therapies available to disrupt the inflammatory process due to lack of appropriate targets. Epsins are a group of proteins that bind clathrin and are involved in the endocytosis of clathrin-coated vesicles. Our studies have shown that epsins expressed in endothelial cells play a major role in the pathogenesis of atherosclerosis. Deletion of the epsin 1 (Epn1) and epsin 2 (Epn2) genes in endothelial cells results in a dramatic reduction in atherosclerotic lesion sizes in apolipoprotein E-deficient (ApoE-/-) mice without affecting systemic hypercholesterolemia. We have also observed that knockdown of both Epn1 and Epn2 with siRNAs affects NF-kB signaling transduction and suppresses both baseline and TNFa-induced VCAM-1 and P-selectin expression in endothelial cells. Therefore, we hypothesize that epsins critically regulate arterial inflammatory responses and consequently potentiate atherosclerotic plaque formation by enhancing TNF-induced NF-kB activation. The role of epsins 1 and 2 in atherosclerosis and molecular mechanisms underlying the arterial inflammatory processes will be characterized using both in vitro and in vivo model systems. In Aim 1, we will investigate molecular mechanisms by which epsins enhance TNF-induced NF-kB signaling in endothelial cells. In Aim 2, we will utilize multifactorial approaches employing both flow cytometry and immunohistochemistry and immunofluorescence to investigate how epsins promote atherogenesis by potentiating endothelial cell activation. These studies will provide mechanistic links between epsins and plaque formation. In Aim 3, we will determine whether targeting epsins in plaques impedes atheroma progression in ApoE-/- mice. These studies will shed light on new pathways that control atherosclerosis and may lead to new treatment of atherosclerosis.