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: 7061619
• 负责人: TRACIE Alexis SEIMON
• 金额: $ 4.88万
• 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/7061619
• 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（由申请人提供）：在晚期动脉粥样硬化斑块中发现巨噬细胞，并且已显示其具有增加的游离胆固醇（FC）积累丰度。FC是一种强有力的巨噬细胞凋亡诱导剂。目的阐明MKK 3/p38 MAPK通路在FC负载的巨噬细胞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MKK 3和p38 α缺陷小鼠的腹膜巨噬细胞将用于询问该信号传导途径是否是胆固醇运输至内质网（ER）的上游，或响应于FC负荷的ER Ca 2+储存的消耗。目的II将使用动脉粥样硬化形成的体内模型确定MKK 3/p38 MAPK通路在动脉粥样硬化病变进展中的作用。将使用与Apoe-/-背景杂交的Mkk 3-/-和p38 α-floxed/LysMCre小鼠来确定阻断MKK 3/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。本提案的主要目的是阐明连接MKK 3/p38 MAPK通路、诱导UPR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。