MOLECULAR PATHOGENESIS OF CHLAMYDIA-INDUCED ATHEROGENESI

描述(改编自申请人的摘要)：目标是定义 衣原体介导的致病机制 动脉硬化。方法将集中在研究信号机制，以 CLP和cHsp60，已知的激活宿主促炎作用的效应分子 小路。要研究的假设是CLP和cHSP60利用 Toll样受体-4(TLR-4)激活巨噬细胞和内皮细胞 核因子-kB和MAPK通过髓系分化蛋白(MyD88)表达。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)、黏附分子(ICAM-1、VCAM-1)、生长因子(M-CSF)、 环氧合酶-2与促进血管内皮细胞迁移 单核细胞；所有与动脉粥样硬化形成有关的因素。这一假设也将是 通过确定apo-E-/-，TLR-4-/-双基因敲除小鼠是否仍存在进行体内测试 对肺炎链球菌诱导的加速病变进展无动于衷。这个 具体目的是：(1)确定TLR-4是否是CLP的信号受体 和cHsp60，并研究诱导的信号通路(ERK1/ERK2， P38MAPK和JNK)和其他导致NK-kB激活的下游事件；(2) 明确CLP和cHsp60诱导的分子机制 单核细胞的跨内皮细胞迁移；以及(3)产生双基因敲除 突变小鼠(TLR4-/-，apoE-/-和mtD88-/-，apoE-/-)研究 TLR-4和MyD88在骨肉瘤发生发展中的作用 存在和不存在肺炎衣原体感染的动脉粥样硬化。这个 这些研究的结果有望导致新的干预目标 和预防冠状动脉粥样硬化。

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.