Mkk3/p38 MAPK, Macrophage Apoptosis, and Atherosclerosis

描述（由申请人提供）：巨噬细胞存在于晚期动脉粥样硬化斑块中，并且已被证明具有增加的游离胆固醇（FC）积累丰度。FC是巨噬细胞凋亡的有效诱导剂。目的：阐明MKK3/p38 MAPK通路在fc负载巨噬细胞中诱导未折叠蛋白反应（UPR）和远端凋亡通路中的作用。来自野生型小鼠或缺乏MKK3和p38 α的小鼠的腹膜巨噬细胞将被用来研究该信号通路是否在胆固醇运输到内质网（ER）的上游，或在FC负荷下消耗ER Ca2+储存。Aim II将通过体内动脉粥样硬化模型确定MKK3/p38 MAPK通路在动脉粥样硬化病变进展中的作用。Mkk3-/-和p38 α -floxed/LysMCre小鼠杂交到Apoe-/-背景将用于确定阻断Mkk3 /p38 MAPK通路是否导致体内巨噬细胞凋亡的抑制，并改变动脉粥样硬化病变形态。本课题的主要目的是阐明MKK3/p38 MAPK通路与UPR诱导的分子机制，并确定该通路是否影响体内巨噬细胞凋亡和动脉粥样硬化。

DESCRIPTION (provided by applicant): Macrophages are found in advanced atherosclerotic plaques, and have been shown to have an increased abundance of free cholesterol (FC) accumulation. FC is a potent inducer of macrophage apoptosis. Aim I will elucidate the role of the MKK3/p38 MAPK pathway in induction of the Unfolded Protein Response (UPR), and distal apoptotic pathways in FC-loaded macrophages. Peritoneal macrophages from wild-type mice, or mice deficient in MKK3 and p38alpha, will be used to ask if this signaling pathway is upstream of cholesterol trafficking to the endoplasmic reticulum (ER), or depletion of ER Ca2+ stores in response to FC loading. Aim II will determine the role of the MKK3/p38 MAPK pathway in atherosclerotic lesion progression using an in-vivo model of atherogenesis. Mkk3-/- and p38alpha-floxed/LysMCre mice crossed onto an Apoe-/- background will be used to determine if blocking the MKK3/p38 MAPK pathway results in inhibition of macrophage apoptosis in-vivo, and alters atherosclerotic lesion morphology. The main objective of this proposal is to elucidate the molecular mechanisms connecting the MKK3/p38 MAPK pathway, induction of the UPR, and determine if this pathway influences macrophage apoptosis and atherosclerosis in-vivo.