Transient Receptor Potential Vanilloid 4 (TRPV4) mediates the host defense and lung injury response to bacterial pneumonia

项目摘要 急性呼吸窘迫综合征（ARDS）是一种以炎性细胞浸润为特征的呼吸系统疾病， 浸润和肺组织损伤，但机制，使巨噬细胞与受伤（僵硬） 解决感染的基质仍然知之甚少。本研究计划调查了 瞬时受体电位香草酸4（TRPV 4），在整合感染性 和基质信号以解决肺炎和相关的肺损伤（ARDS）。我们学习的长期目标 是确定一个治疗靶点，以提高感染相关的ARDS的解决。我们的初步数据 显示TRPV 4信号通过p38 MAPK整合基质和感染信号，以增强 巨噬细胞吞噬作用和抗炎细胞因子产生。因此，我们提出了小说 假设：TRPV 4启动的信号转导整合了细胞外基质硬度和LPS信号，因此 介导宿主防御和对细菌性肺炎的肺损伤反应的关键要素。这一假设 将通过三个相互关联但独立的具体目标进行测试：（1）确定分子 TRPV 4信号整合细胞外基质硬度和LPS信号的机制， 增强巨噬细胞吞噬作用和抗炎细胞因子的产生;（2）确定 TRPV 4在a）肺细菌清除、B）感染诱导的肺损伤和c）肺损伤中的意义 在小鼠慢性细菌性肺炎中的缓解;和（3）确定TRPV 4在 吞噬作用和抗炎细胞因子的产生。我们的建议是 创新的概念，因为它是第一个涉及基质硬度敏感阳离子通道（TRPV 4）， 内毒素介导的巨噬细胞吞噬作用。这项研究具有重要意义，因为它可能会发现新的 治疗感染相关的ARDS的治疗靶点。这项研究将在博士的实验室进行。 Olman，Lerner研究所（LRI），克利夫兰诊所，并将由免疫调节专家提供建议 和肺损伤。沿着我的导师，顾问团已经创建了一个结构化的职业发展 计划，包括免疫学，细胞生物学和转化研究的正式课程。一个理想 知识和环境是在LRI的地方。我的职业目标是建立和领导一个独立的研究 该计划将促进肺损伤，修复和纤维化领域的科学知识和患者护理。 我对研究的承诺，强有力的指导，我的机构致力于培养下一代 医生科学家和环境将允许我建立一个医生科学家的职业生涯。

PROJECT SUMMARY Infection-associated acute respiratory distress syndrome (ARDS) is characterized by inflammatory cell infiltration and lung tissue injury, but the mechanism whereby the macrophage interacts with the injured (stiff) matrix to resolve the infection remains poorly understood. This research proposal investigates the role of the mechanosensitive ion channel, Transient receptor potential vanilloid 4 (TRPV4), in integrating the infectious and matrix signals to resolve pneumonia and associated lung injury (ARDS). The long-term goal of our studies is to identify a therapeutic target to enhance resolution of infection-associated ARDS. Our preliminary data show that the TRPV4 signal integrates the matrix and infectious signals through p38 MAPK to enhance macrophage phagocytosis and anti-inflammatory cytokine production. Therefore, we proposed the novel hypothesis: TRPV4 initiated signaling integrates the extracellular matrix stiffness and LPS signals, therefore mediating key elements of the host defense and lung injury response to bacterial pneumonia. This hypothesis will be tested through three interrelated, but independent specific aims: (1) to determine the molecular mechanism whereby TRPV4 signals integrate the extracellular matrix stiffness and LPS signals to enhance macrophage phagocytosis and anti-inflammatory cytokine production; (2) to determine the significance of TRPV4 in a) lung bacterial clearance, b) infection-induced lung injury, and c) lung injury resolution in chronic bacterial pneumonia in mice; and (3) to determine the role of TRPV4 in phagocytosis and anti-inflammatory cytokine production in human macrophages. Our proposal is innovative in concept as it is the first to implicate a matrix stiffness-sensing cation channel (TRPV4) in endotoxin-mediated macrophage phagocytosis. The proposed research is significant as it may discover novel therapeutic targets to treat infection-associated ARDS. This research will be performed in the laboratory of Dr. Olman, Lerner Research Institute (LRI), Cleveland Clinic, and will be advised by experts in immune regulation and lung injury. Along with my mentor, the advisory panel has created a structured career development program, including formal coursework in immunology, cell biology, and translational research. An ideal intellectual and environment is in place at the LRI. My career goal is to build and lead an independent research program that will advance scientific knowledge and patient care in the field of lung injury, repair, and fibrosis. My commitments to research, strong mentorship, dedication of my institution to training the next generation of physician scientists, and environment will allow me to build a career as a physician scientist.