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.
Project 1 of this Program seeks to define the properties of a calcium-permeable plasma membrane channel on lung endothelial cells that is acfivated by the interaction of endothelial cells with activated circulating neutrophils. We will study the role that this interacfion and channel acfivafion has on inflammatory injury in the lung vasculature and identify potential therapeutic targets in the signaling pathways.
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|Di, Anke; Xiong, Shiqin; Ye, Zhiming et al. (2018) The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation. Immunity 49:56-65.e4|
|Dai, Zhiyu; Zhu, Maggie M; Peng, Yi et al. (2018) Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension. Am J Respir Crit Care Med 198:788-802|
|Marsboom, Glenn; Chen, Zhenlong; Yuan, Yang et al. (2017) Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension. Mol Biol Cell 28:1177-1185|
|Mittal, Manish; Nepal, Saroj; Tsukasaki, Yoshikazu et al. (2017) Neutrophil Activation of Endothelial Cell-Expressed TRPM2 Mediates Transendothelial Neutrophil Migration and Vascular Injury. Circ Res 121:1081-1091|
|Yamada, Kaori H; Kang, Hojin; Malik, Asrar B (2017) Antiangiogenic Therapeutic Potential of Peptides Derived from the Molecular Motor KIF13B that Transports VEGFR2 to Plasmalemma in Endothelial Cells. Am J Pathol 187:214-224|
|Zhang, Lianghui; Jambusaria, Ankit; Hong, Zhigang et al. (2017) SOX17 Regulates Conversion of Human Fibroblasts Into Endothelial Cells and Erythroblasts by Dedifferentiation Into CD34+Progenitor Cells. Circulation 135:2505-2523|
|Yazbeck, Pascal; Tauseef, Mohammad; Kruse, Kevin et al. (2017) STIM1 Phosphorylation at Y361 Recruits Orai1 to STIM1 Puncta and Induces Ca2+ Entry. Sci Rep 7:42758|
|Wu, Chaomin; Evans, Colin E; Dai, Zhiyu et al. (2017) Lipopolysaccharide-induced endotoxemia in corn oil-preloaded mice causes an extended course of lung injury and repair and pulmonary fibrosis: A translational mouse model of acute respiratory distress syndrome. PLoS One 12:e0174327|
|Dai, Zhiyu; Zhao, You-Yang (2017) Discovery of a murine model of clinical PAH: Mission impossible? Trends Cardiovasc Med 27:229-236|
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