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

• 批准号: 10334426
• 负责人: Rachel Greenberg Scheraga
• 金额: $ 42.91万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 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/10334426
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Alveolar; Alveolar Macrophages; Alveolus; Bacterial Pneumonia; Binding; Binding Proteins; Cations; Cell membrane; Cell physiology; Cells; Chronic; Complex; 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 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; Tail; Testing; Tissues; United States National Institutes of Health; Vanilloid; alveolar epithelium; base; biophysical properties; cytokine; design; effective therapy; epithelial injury; in vivo; in vivo Model; injured; innovation; interstitial; loss of function; lung injury; macrophage; 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

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.

项目摘要/摘要 压倒性细菌肺炎损伤并僵硬，导致急性呼吸窘迫综合征 （ARDS）死亡率高达50％。鉴于许多药物治疗失败，ARDS管理 得到支持。 ARDS是内皮和肺泡上皮损伤的结果，然后是招募和 受伤肺泡中炎症细胞的积累。巨噬细胞是肺中的关键效应细胞 通过吞噬入侵的病原体和分泌细胞因子来损伤过程。我们已经确定 机械敏感的离子通道，瞬态接收器电势香草素4（TRPV4），可保护肺免受损伤 通过MAPK的新机制的慢性假单胞菌铜绿肺炎的体内模型 分子切换，从JNK到p38。但是，将TRPV4连接到的关键细胞内信号分子 MAPK分子开关和精确的细胞表型/功能增加了吞噬作用/细菌清除率 爆炸肺损伤尚不清楚。发现控制的新型机械签名机制 当肺部受伤/僵硬时，巨噬细胞功能将满足设计治疗疗法的未满足的医疗需求 这种毁灭性的疾病。该研究提案研究了TRPV4适应宿主的机制 防御可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 推断巨噬细胞中依赖TRPV4的细胞内信号，以保护和解决肺炎 - 相关的肺损伤。我们的初步数据表明，巨噬细胞TRPV4通过特定细胞内信号 信号分子在体外改变巨噬细胞活化反应。因此，我们提出了小说 假设：TRPV4量身定制宿主反应以保护肺炎肺炎肺炎肺炎 通过巨噬细胞内信号。该假设将通过三个相互关联进行检验，但 独立的特定目的：（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 生产和（3）比较TrPv4在细菌中牙间巨噬细胞中的作用 铜绿假单胞菌肺炎在小鼠中清除和感染引起的肺损伤。我们的建议是 概念上的创新性是第一个隐含矩阵刚度感应阳离子渠道（TRPV4）及其 细菌肺炎和相关肺组织损伤中的细胞内信号传导分子。提议 研究很重要，并且与NIH的使命相关，我们的目标是探索巨噬细胞中的TRPV4 整合感染和基质机械信号传导以保护肺部免受损伤。发现的路径 将确定新的治疗靶标，以治疗与感染相关的ARDS。