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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Illinois at Chicago
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Yan, Qian; Sun, Lei; Zhu, Ziyan et al. (2014) Jmjd3-mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages. Cell Signal 26:1783-91
Huang, Xiaojia; Sun, Kai; Zhao, Yidan D et al. (2014) Human CD34+ progenitor cells freshly isolated from umbilical cord blood attenuate inflammatory lung injury following LPS challenge. PLoS One 9:e88814
He, Hui-Qiong; Troksa, Erica L; Caltabiano, Gianluigi et al. (2014) Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands. J Biol Chem 289:2295-306
Gu, Xiaowu; Fliesler, Steven J; Zhao, You-Yang et al. (2014) Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration. Am J Pathol 184:541-55
Zhou, Jun-xian; Liao, Dan; Zhang, Shuo et al. (2014) Chemerin C9 peptide induces receptor internalization through a clathrin-independent pathway. Acta Pharmacol Sin 35:653-63
Bachmaier, Kurt; Toya, Sophie; Malik, Asrar B (2014) Therapeutic administration of the chemokine CXCL1/KC abrogates autoimmune inflammatory heart disease. PLoS One 9:e89647
DebRoy, Auditi; Vogel, Stephen M; Soni, Dheeraj et al. (2014) Cooperative signaling via transcription factors NF-?B and AP1/c-Fos mediates endothelial cell STIM1 expression and hyperpermeability in response to endotoxin. J Biol Chem 289:24188-201
Hecquet, Claudie M; Zhang, Min; Mittal, Manish et al. (2014) Cooperative interaction of trp melastatin channel transient receptor potential (TRPM2) with its splice variant TRPM2 short variant is essential for endothelial cell apoptosis. Circ Res 114:469-79
Cai, Lei; Yi, Fan; Dai, Zhiyu et al. (2014) Loss of caveolin-1 and adiponectin induces severe inflammatory lung injury following LPS challenge through excessive oxidative/nitrative stress. Am J Physiol Lung Cell Mol Physiol 306:L566-73
Zhao, Yidan D; Huang, Xiaojia; Yi, Fan et al. (2014) Endothelial FoxM1 mediates bone marrow progenitor cell-induced vascular repair and resolution of inflammation following inflammatory lung injury. Stem Cells 32:1855-64

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