TRPV4 Regulates Mechanosensitive Macrophage Functions in Lung Injury

TRPV4 调节肺损伤中的机械敏感巨噬细胞功能

基本信息

批准号：
10557173
负责人：
Rachel Greenberg Scheraga
金额：
$ 42.55万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557173
关键词：
Acute Respiratory Distress Syndrome Alveolar Alveolar Macrophages Alveolus Bacterial Pneumonia Binding Binding Proteins Cations Cell membrane Cell physiology Cells Chronic Complex Cytoprotection Cytoskeleton Data Disease Effector Cell Endothelium Goals Heterogeneity Homeostasis Host Defense Human IRAK1 gene Immune Immune response In Vitro Individual Infection Inflammatory Injury Invaded Ion Channel Knockout Mice Link Location Lung MAP Kinase Gene MAPK8 gene Macrophage Macrophage Activation Mechanics Medical Mission Modeling Molecular Mus Pathway interactions Phagocytes Phagocytosis Pharmacological Treatment Phenotype Pneumonia Process Production Property Proteins Proteomics Pseudomonas aeruginosa Pseudomonas aeruginosa pneumonia Publishing Research Research Proposals Role Signal Pathway Signal Transduction Signaling Molecule Structure of parenchyma of lung System TLR4 gene TRPV channel Tail Testing Tissues United States National Institutes of Health Vanilloid alveolar epithelium biophysical properties cytokine design effective therapy epithelial injury in vivo in vivo Model injured innovation interstitial loss of function lung injury mechanical properties mechanical signal monocyte mortality new therapeutic target novel novel therapeutics p38 Mitogen Activated Protein Kinase p65 pathogen receptor recruit response response to injury targeted treatment therapy design tissue injury

项目摘要

PROJECT SUMMARY/ABSTRACT Overwhelming bacterial pneumonia injures and stiffens the lung leading to acute respiratory distress syndrome (ARDS) that carries a mortality of up to 50%. Given many failed pharmacologic treatments, ARDS management is supportive. ARDS is a consequence of endothelial and alveolar epithelial injury followed by recruitment and accumulation of inflammatory cells in the injured alveolus. Macrophages are the key effector cells in the lung injury process by phagocytizing invading pathogens and secreting cytokines. We have identified that the mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), protects the lung from injury in an in vivo model of chronic Pseudomonas aeruginosa pneumonia through a novel mechanism of MAPK molecular switching, from JNK to p38. However, the key intracellular signaling molecules that link TRPV4 to the MAPK molecular switch and the precise cell phenotype/function that increases phagocytosis/bacterial clearance and decreases lung injury are unknown. Uncovering novel mechanosensitive signaling mechanisms that control macrophage function when the lung is injured/stiff will fulfill the unmet medical need to design therapies to treat this devastating disease. This research proposal investigates the mechanism whereby TRPV4 adapts the host defense to enhance the lung injury response to P. aeruginosa pneumonia. The long-term goal of our studies is to deduce TRPV4-dependent intracellular signals in macrophages that protect and resolve pneumonia- associated lung injury. Our preliminary data show that macrophage TRPV4 signals through specific intracellular signaling molecules to alter the macrophage activation response in vitro. Therefore, we propose the novel hypothesis: TRPV4 tailors the host response to protect the lung from injury after P. aeruginosa pneumonia through macrophage intracellular signals. This hypothesis will be tested through three interrelated, but independent specific aims: (1) to determine the mechanism whereby TRPV4 enhances macrophage phagocytosis, (2) to determine the mechanism whereby TRPV4 limits pro-inflammatory cytokine production, and (3) to compare the role of TRPV4 in alveolar vs interstitial macrophages in bacterial clearance and infection-induced lung injury after P. aeruginosa pneumonia in mice. Our proposal is innovative in concept as it is the first to implicate a matrix stiffness-sensing cation channel (TRPV4) and its intracellular signaling molecules in bacterial pneumonia and associated lung tissue injury. The proposed research is significant and relevant to the NIH’s mission as we aim to explore how TRPV4 in macrophages integrates the infection and matrix mechanical signaling to protect the lung from injury. The pathways discovered will identify novel therapeutic targets to treat infection-associated ARDS.

项目概要/摘要压倒性的细菌性肺炎会损伤肺部并使其僵硬，导致急性呼吸窘迫综合征由于药物治疗失败，ARDS 的死亡率高达 50%。 ARDS 是内皮和肺泡上皮损伤以及随后的募集和损伤的结果。受损肺泡中炎症细胞的积累，巨噬细胞是肺部的关键效应细胞。通过吞噬入侵的病原体并分泌细胞因子来损伤过程。机械敏感离子通道、瞬时受体电位香草酸 4 (TRPV4) 可保护肺免受损伤通过 MAPK 的新机制建立慢性铜绿假单胞菌肺炎体内模型分子转换，从 JNK 到 p38 然而，连接 TRPV4 和 p38 的关键细胞内信号分子。 MAPK 分子开关和增加吞噬作用/细菌清除的精确细胞表型/功能并减少肺损伤的发现尚不清楚。肺部受伤/僵硬时的巨噬细胞功能将满足设计疗法来治疗的未满足的医疗需求这项研究计划调查了 TRPV4 适应宿主的机制。防御以增强对铜绿假单胞菌肺炎的肺损伤反应。我们研究的长期目标是。推断巨噬细胞中 TRPV4 依赖性细胞内信号，可保护和解决肺炎 - 我们的初步数据表明巨噬细胞 TRPV4 通过特定的细胞内信号传导。因此，我们提出了这种新的信号分子来改变体外巨噬细胞的激活反应。假设：TRPV4 调整宿主反应以保护肺部免受铜绿假单胞菌肺炎后的损伤通过巨噬细胞细胞内信号，该假设将通过三个相互关联的但被检验。独立的具体目标：（1）确定TRPV4增强巨噬细胞的机制吞噬作用，(2) 确定 TRPV4 限制促炎细胞因子的机制 (3) 比较 TRPV4 在细菌中肺泡巨噬细胞与间质巨噬细胞中的作用小鼠铜绿假单胞菌肺炎后的清除和感染引起的肺损伤。概念上的创新，因为它是第一个暗示基质刚度传感阳离子通道（TRPV4）及其细菌性肺炎和相关肺组织损伤中的细胞内信号分子。这项研究具有重要意义，并且与 NIH 的使命相关，因为我们的目标是探索 TRPV4 在巨噬细胞中的作用整合感染和基质机械信号以保护肺部免受损伤。将确定治疗感染相关 ARDS 的新治疗靶点。