PMN-Endothelial Cross-Talk via TRPM2 and Lung Vascular Injury

通过 TRPM2 的中性粒细胞内皮串扰和肺血管损伤

• 批准号: 8521343
• 负责人: Asrar B. Malik
• 金额: $ 32.11万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8521343
• 关键词: Acute Lung Injury; Address; Adherens Junction; Adhesions; Binding; Blood Vessels; CD18 Antigens; Calcium; Cell Communication; Cell membrane; Chemotactic Factors; Coculture Techniques; Complex; Data; Endothelial Cells; Endothelium; Event; Functional disorder; Generations; Hydrogen Peroxide; Infiltration; Inflammatory; Injury; Integral Membrane Protein; Integrin Binding; Integrins; Intercellular adhesion molecule 1; Ion Channel; Lipopolysaccharides; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; NF-kappa B; Oxidants; Pathway interactions; Permeability; Phosphorylation; Physiological; Property; Protein Isoforms; RNA Splicing; Reactive Oxygen Species; Regulation; Role; Sepsis; Signal Pathway; Signal Transduction; Testing; Variant; Vascular Permeabilities; base; cadherin 5; insight; lung injury; lung vascular injury; methionyl-leucyl-phenylalanine; monolayer; neutrophil; novel; programs; receptor; therapeutic target

The central objective of Project 1 is to define the properties of the novel, oxidant-sensitive transient receptor potenfial melastafin (TRPM)2, a Ca(2+)-permeable channel in lung endothelial cells (ECs), how it regulates Ca(2+) signaling, and its role in the mechanism of neutrophil-dependent increases in lung vascular permeability and infiammatory injury. Our approach will be to identify the essenfial role of neutrophil-EC interactions in activafing the TRPM2 channel, then its mechanism of activation, and finally define how TRPM2 activation leads to increased lung endothelial permeability and transmigration of PMNs at the level of adherens juncfions. Aim #1 will test the hypothesis that PMN interaction with the lung endothelium via beta2-integrin/ICAM-1 binding increases lung vascular permeability through the activation of TRPM2 channels in ECs. Aim #2 will define the role of the short splice variant of TRPM2, TRPM2-S. in regulafing TRPM2-mediated Ca2+ entry in lung ECs and in the mechanism of endothelial hyper-permeability and PMN transmigration. Aim #3 will determine the role of NF-kappaB-dependent ICAM-1 expression in amplifying TRPM2 acfivity in ECs and thereby in mediating PMN-dependent lung infiammatory injury. The proposed studies will use molecular, genefic. and physiological approaches in EC monolayers co-cultured with PMNs and mouse lung models (including the recentiy developed TRPM2(-/-) mice). These data will provide new insights into the mechanisms of acute lung injury and specifically theTRPM2-activated pathways that mediate lung injury. Furthermore, we believe that it will be possible, with a new understanding of this transcellular cross-talk, to block inappropriate neutrophil-EC interacfions and PMN-mediated lung injury by interfering with TRPM2-activated signaling pathways.

The central objective of Project 1 is to define the properties of the novel, oxidant-sensitive transient receptor potenfial melastafin (TRPM)2, a Ca(2+)-permeable channel in lung endothelial cells (ECs), how it regulates Ca(2+) signaling, and its role in the mechanism of neutrophil-dependent increases in lung vascular permeability and infiammatory injury.我们的方法是确定嗜中性粒细胞相互作用在激活TRPM2通道，然后是其激活机制中的典型作用，并最终定义TRPM2激活如何导致肺内皮通透性和PMN在Adherens Juncctions水平上的肺内皮渗透性和PMN的移动。 AIM＃1将检验以下假设：PMN通过beta2-凝集素/ICAM-1结合与肺内皮相互作用通过ECS中TRPM2通道的激活来增加肺血管通透性。 AIM＃2将定义TRPM2，TRPM2-S的短剪接变体的作用。在调节肺EC中的TRPM2介导的Ca2+进入中，以及内皮过度渗透性和PMN转移的机理。 AIM＃3将确定NF-KAPPAB依赖性ICAM-1表达在EC中扩增TRPM2抗性中的作用，从而在介导PMN依赖性的肺部侵害性损伤中的作用。拟议的研究将使用分子基因。以及与PMN共同培养的EC单层中的生理方法 和小鼠肺模型（包括最近开发的TRPM2（ - / - ）小鼠）。这些数据将提供有关急性肺损伤机制的新​​见解，特别是介导肺损伤的THETRPM2激活途径。此外，我们认为，通过对这种跨细胞串扰的新理解，可以通过干扰TRPM2激活的信号传导途径来阻止不适当的中性粒细胞ICECTIONS和PMN介导的肺损伤。