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: 6537946
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537946
• 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（改编自申请人的摘要）：目标是定义 导致衣原体介导的发展和进展的机制 动脉粥样硬化。方法将集中于研究信号机制 cLPS 和 cHsp60，已知可激活宿主促炎症的效应分子 途径。要研究的假设是 cLPS 和 cHsp60 利用 Toll 样受体 4 (TLR-4) 通过激活巨噬细胞和内皮细胞 NF-kB 和 MAPK 通过骨髓分化蛋白 (MyD88) 发挥作用。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)、 环加氧酶-2 (Cox-2) 和增强的跨内皮细胞迁移 单核细胞；与动脉粥样硬化形成有关的所有因素。假设也将是 通过确定 apo-E-/-、TLR-4-/- 双敲除小鼠是否仍然存在进行体内测试 对肺炎衣原体引起的加速病变进展漠不关心。这 具体目标是 (1) 确定 TLR-4 是否是 cLPS 的信号传导受体 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) 定义参与 cLPS 和 cHsp60 诱导的分子机制 单核细胞跨内皮细胞迁移； (3) 创造双淘汰赛 小鼠突变体（TLR4-/-、apoE-/- 和 MtD88-/-、apoE -/-）以研究 TLR-4 和 MyD88 在疾病发生和进展中的贡献 存在或不存在肺炎衣原体感染时的动脉粥样硬化。这 这些研究的结果预计将导致新的干预目标 以及预防冠状动脉粥样硬化。