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，血管壁内皮细胞和平滑肌细胞（SMC） 一个复杂的和高度调节的先天免疫系统的一部分，调节炎症信号， 动脉粥样硬化我们发现人冠状动脉平滑肌细胞（HCASMC）表达膜结合的 CD 14是一种模式识别受体，在先天性免疫转导中起核心作用。 炎症细胞对内毒素和其他细菌产物的反应。我们还发现 表面活性蛋白D（SP-D）在血管细胞中的表达，SP-D是蛋白质聚集蛋白家族的成员 结合内毒素和CD 14以调节肺中的先天免疫应答。使用组合 药理学，分子和基因为基础的方法，我们建议：1。测试的假设 SMC中的CD 14在将免疫应答转导至多种炎症介质中起核心作用。我们 我们将鉴定HCASMC中的CD 14配体，我们将研究HCASMC中CD 14表达的调节， 人冠状动脉内皮细胞通过氧化应激和激活PPAR-gamma。我们还将 确定CD 14连接是否调节SMC中清道夫受体的表达和功能。2L 检验SP-D调节血管细胞中CD 14介导的促炎信号传导的假设。 我们建议研究SP-D阻断血管细胞中促炎信号传导的机制， 重点关注SP-D与内毒素和细胞信号蛋白的结合作用。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 CD 14和SP-D调节apoE-/-小鼠动脉粥样硬化假说使用CD 14-/-和SP-DV-/-小鼠 与apoE-/-小鼠杂交以产生双敲除小鼠，我们将检查 动脉粥样硬化、血管炎症和内皮功能障碍， 用低水平内毒素反复刺激先天免疫系统。在一起，拟议的 研究将为CD 14在血管炎症中的潜在关键作用提供新的见解， 通过氧化应激和PPAR-gamma调节血管壁中的CD 14表达。此外，拟议的 这些研究将是首次研究SP-D在血管壁中的潜在免疫调节作用。 这些研究将有助于阐明血管壁细胞导致炎症的机制 现在已知是动脉粥样硬化的重要原因。此外，我们的发现可能会导致新的 治疗动脉粥样硬化炎性成分的方法。