CD14, Surfactant Proteins, and Vascular Inflammation

CD14、表面活性蛋白和血管炎症

• 批准号: 7160705
• 负责人: Neal L Weintraub
• 金额: $ 33.94万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7160705
• 关键词: anticoagulants; antioxidants; atherosclerosis; cardiovascular disorder risk; endotoxins; enzyme mechanism; extracellular; genetically modified animals; heparin; inflammation; isozymes; laboratory mouse; muscle function; nitric oxide; oxidative stress; pathologic process; protein C; protein structure; remission /regression; smooth muscle; superoxide dismutase; thrombosis; vascular endothelium

The central hypothesis of this project is that vascular wall endothelial and smooth muscle cells (SMC) are part of a complex and highly regulated innate immune system that modulates inflammatory signaling in atherosclerosis. We have discovered that human coronary artery SMC (HCASMC) express membranebound CD14, a pattern recognition receptor that plays a central role in transducing innate immune responses to endotoxin and other bacterial products in inflammatory cells. We have also detected expression in vascular cells of surfactant protein D (SP-D), a member of the collectin family of proteins that binds to endotoxin and CD14 to modulate innate immune responses in the lung. Using a combination of pharmacological, molecular, and gene-based approaches, we propose to: 1. Test the hypothesis that CD14 in SMC plays a central role in transducing immune responses to multiple inflammatory mediators. We will identify CD14 ligands in HCASMC, and we will examine regulation of CD14 expression in HCASMC and human coronary artery endothelial cells by oxidative stress and activation of PPAR-gamma. We will also determine whether CD14 ligation modulates expression and function of scavenger receptors in SMC. 2L Test the hypothesis that SP-D modulates CD14-mediated pro-inflammatory signaling in vascular cells. We propose to examine mechanisms whereby SP-D blocks pro-inflammatory signaling in vascular cells, focusing on the role of binding of SP-D to endotoxin and cell signaling proteins. We will also determine whether SP-D expression is regulated by inflammatory mediators and/or oxidative stress. 3. Test the hypothesis that CD14 and SP-D modulate atherosclerosis in apoE-/- mice. Using CD14-/- and SP-DV-/- mice cross-bred with apoE-/- mice to create double knockout mice, we will examine the extent of atherosclerosis, vascular inflammation, and endothelial dysfunction in the absence and presence of recurrent challenges with low-level endotoxin to stimulate the innate immune system. Together, the proposed studies will provide novel insight into the potentially critical role of CD14 in vascular inflammation, and modulation of CD14 expression in the vascular wall by oxidant stress and PPAR-gamma. Further, the proposed studies will be the first to investigate the potential immunomodulatory role of SP-D in the vascular wall. These studies will help to elucidate mechanisms whereby vascular wall cells contribute to inflammation now known to be an important cause of atherosclerosis. Further, our findings may lead to new approaches to treating the inflammatory component of atherosclerosis.

该项目的中心假设是血管壁内皮和平滑肌细胞（SMC）是 复杂且高度调节的先天免疫系统的一部分，该系统调节炎症信号传导 动脉粥样硬化。我们发现人类冠状动脉SMC（HCASMC）Express MembraneBound CD14，一种模式识别受体，在传递先天免疫中起着核心作用 对炎性细胞中内毒素和其他细菌产物的反应。我们还检测到 表面活性剂蛋白D（SP-D）的血管细胞中的表达，蛋白质的收集蛋白家族的成员 与内毒素和CD14结合以调节肺中的先天免疫反应。使用组合 在药理，分子和基因方法的方法中，我们提出：1。检验以下假设： SMC中的CD14在传递对多个炎症介质的免疫反应中起着核心作用。我们 将在HCASMC中识别CD14配体，我们将检查HCASMC和 人类冠状动脉内皮细胞通过氧化应激和PPAR-GAMMA的激活。我们也会 确定CD14连接是否调节了SMC中的清道夫受体的表达和功能。 2L 测试SP-D调节血管细胞中CD14介导的促炎信号传导的假设。 我们建议检查机制，从而使SP-D阻止血管细胞中的促炎信号传导， 侧重于SP-D与内毒素和细胞信号蛋白结合的作用。我们还将确定 SP-D表达是否受炎症介质和/或氧化应激调节。 3。测试 假设CD14和SP-D调节APOE - / - 小鼠的动脉粥样硬化。使用CD14 - / - 和SP-DV - / - 小鼠 与apoe - / - 小鼠杂交以创建双基因敲除小鼠，我们将检查 动脉粥样硬化，血管炎症和内皮功能障碍在不存在和存在下 低级内毒素刺激先天免疫系统的反复挑战。一起，提议 研究将为CD14在血管炎症中的潜在至关重要作用提供新的见解，以及 通过氧化应激和PPAR-GAMMA对CD14表达的调节。此外，提议 研究将是第一个研究SP-D在血管壁中潜在的免疫调节作用的研究。 这些研究将有助于阐明血管壁细胞有助于炎症的机制 现在已知是动脉粥样硬化的重要原因。此外，我们的发现可能导致新 治疗动脉粥样硬化的炎症成分的方法。