Mkk3/p38 MAPK, Macrophage Apoptosis, and Atherosclerosis

Mkk3/p38 MAPK、巨噬细胞凋亡和动脉粥样硬化

• 批准号: 6885044
• 负责人: TRACIE Alexis SEIMON
• 金额: $ 4.4万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-07 至 2008-06-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885044
• 关键词: apoptosis; atherosclerosis; biological signal transduction; blood lipoprotein; calcium ion; endoplasmic reticulum; laboratory mouse; macrophage; mitogen activated protein kinase; phosphorylation; postdoctoral investigator; protein folding

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.

描述(申请人提供)：巨噬细胞在晚期动脉粥样硬化斑块中被发现，并已被证明有更多的游离胆固醇(FC)积累。FC是一种有效的巨噬细胞凋亡诱导剂。目的阐明MKK3/p38MAPK通路在Fc负载巨噬细胞的未折叠蛋白反应(UPR)和远端凋亡通路中的作用。来自野生型小鼠或缺乏MKK3和p38α的小鼠的腹膜巨噬细胞将被用来询问这一信号通路是否在胆固醇运输到内质网(ER)的上游，或响应FC负荷而耗尽ER钙存储。目的利用动脉粥样硬化的体内模型，研究MKK3/p38MAPK通路在动脉粥样硬化病变进展中的作用。MKK3-/-和p38Alpha-Floxed/LysMCre小鼠将被用于确定阻断MKK3/p38MAPK通路是否会导致体内巨噬细胞凋亡的抑制，并改变动脉粥样硬化病变的形态。本研究的主要目的是阐明MKK3/p38MAPK通路与UPR的诱导相关的分子机制，并确定该通路是否影响体内巨噬细胞的凋亡和动脉粥样硬化。