MOLECULAR PATHOGENESIS OF CHLAMYDIA-INDUCED ATHEROGENESI

衣原体引起的动脉粥样硬化的分子发病机制

• 批准号: 6729065
• 负责人: Moshe Arditi
• 金额: $ 38.25万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729065
• 关键词: Chlamydiaceae; atherosclerosis; biological signal transduction; cell adhesion molecules; cell migration; disease /disorder etiology; gene targeting; heat shock proteins; laboratory mouse; leukocyte activation /transformation; lipopolysaccharides; macrophage; membrane proteins; mitogen activated protein kinase; molecular pathology; nuclear factor kappa beta; receptor; vascular endothelium

DESCRIPTION (Adapted from the Applicant's Abstract): The goal is to define mechanisms leading to the development and progression of chlamydiae-mediated atherosclerosis. Approaches will center on studying signaling mechanisms for cLPS and cHsp60, effector molecules known to activate host pro-inflammatory pathways. The hypothesis to be investigated is that cLPS and cHsp60 utilize the Toll-like Receptor-4 (TLR-4) to activate macrophages and endothelial cells via NF-kB and MAPK through myeloid differentiation protein (MyD88). The effects of this activation will lead to increased expression of pro-inflammatory cytokines (IL-6, IL-8), adhesion molecules (ICAM-1 VCAM-1), growth factors (M-CSF), cyclooxygenase-2 (Cox-2) and enhanced transendothelial cell migration of monocytes; all factors implicated in atherogenesis. The hypothesis also will be tested in vivo by determining if apo-E-/-, TLR-4-/- double knockout mice remain indifferent to C. pneumoniae-induced accelerated lesion progression. The specific aims are to (1) determine if TLR-4 is the signaling receptor for cLPS and cHsp60 and to investigate the signaling pathways induced (ERK1/ERK2, p38MAPK and JNK) and other down-stream events leading to NK-kB activation; (2) to define the molecular mechanisms involved in cLPS and cHsp60-induced transendothelial cell migration of monocytes; and (3) to create double knockout mutants in mice (TLR4-/-, apoE-/- and MtD88-/-, apoE -/-) to investigate the contributions of TLR-4 and MyD88 in the initiation and progression of atherosclerosis in the presence and absence of C. pneumoniae infection. The results of these studies are expected to lead to new targets for intervention and prevention of coronary atherosclerosis.

描述（改编自申请人摘要）：目标是定义 导致衣原体介导的 动脉粥样硬化方法将集中在研究信号机制， cLPS和cHsp 60，已知激活宿主促炎性细胞因子的效应分子 途径。待研究的假设是cLPS和cHsp 60利用了 Toll样受体-4（TLR-4）通过激活巨噬细胞和内皮细胞 NF-kB和MAPK通过髓样分化蛋白（MyD 88）。的影响 这种激活将导致促炎细胞因子的表达增加 (IL-6，IL-8），粘附分子（ICAM-1，VCAM-1），生长因子（M-CSF）， 环氧合酶-2（考克斯-2）和增强的跨内皮细胞迁移 单核细胞;所有与动脉粥样硬化形成有关的因素。假设也将是 通过测定apo-E-/-、TLR-4-/-双敲除小鼠是否仍存在 对C漠不关心。肺炎引起的加速病变进展。的 具体目的是（1）确定TLR-4是否是cLPS的信号受体 和cHsp 60并研究诱导的信号传导途径（ERK 1/ERK 2， p38 MAPK和JNK）以及其他导致NK-kB激活的下游事件;（2） 为了确定cLPS和cHsp 60诱导的细胞凋亡的分子机制， 单核细胞的跨内皮细胞迁移;和（3）产生双敲除 突变体（TLR 4-/-，apoE-/-和MtD 88-/-，apoE -/-），以研究 TLR-4和MyD 88在肿瘤发生和发展中的作用 动脉粥样硬化的存在和不存在C.肺炎感染。的 这些研究的结果预计将导致新的干预目标 和预防冠状动脉粥样硬化。