The central objective of the Program Project renewal is to define critical mechanisms mediating neutrophil (PMN) and endothelial activation that induce lung inflammation and vascular injury and lead to protein-rich pulmonary edema and acute lung injury (ALI) and specific mechanisms that lead to recovery. The Program Project is based on the premise that activation of specific signaling pathways in the PMN and the endothelium set into motion events that produce inflammation and, if left unchecked, lead to endothelial injury and tissue edema. In Project 1 Dr. Asrar Malik, P.I., and colleagues will address the concept that cross-talk between PMNs and ECs via NADPH oxidase-derived oxidants is critical in signaling the gating of the novel, oxidant-sensitive transient receptor potential melastatin (TRPM)-2, a Ca++-permeable channel abundant in lung endothelial cells. They will test the postulate that this channel is critical in the mechanism of lung injury. In Project 2 the P.I., Dr. Richard Ye, together with his colleagues, will explore their recent discovery that MAP kinase phosphatase 5 (MKP5) is required for the negative regulation of the phagocyte NADPH oxidase, and thereby modulation of lung injury. This project will test the postulate of this pathway in lung injury. In Project 3 Dr. C. Tiruppathi, P.I. will study the currently uncharacterized but potentially significant role of the transcriptional repressor protein, Dream, as a negative master regulator of the dual function deubiquitinating/E3 ligase enzyme A20, which has a central role in preventing NF-kappaB activation. In Project 4, Dr. Y. Y. Zhao, P.I. will address the role of the Forkhead transcription factor FoxM1 in the repair of endothelial adherens junctions and in the regeneration of the endothelial monolayer after lung vascular injury. We are convinced that a concerted effort as described in this program will lead to a new understanding of the signaling mechanisms responsible for lung inflammatory injury and recovery, which is essential for developing more rational therapeutic strategies based on the underlying pathobiology of lung inflammatory injury and ALI.

Public Health Relevance

This Program Project seeks to identify important signaling pathways that cause and those that reverse activation of inflammatory cells and their interaction with and activation of cells in lung blood vessels. These interactions can lead to lung inflammation and acute lung injury (ALI). Our group will study how the cells signal each other so that we may identify therapeutic targets for drug discovery and the treatment of ALI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL077806-09
Application #
8521342
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Moore, Timothy M
Project Start
2004-07-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$1,744,597
Indirect Cost
$633,389
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Di, Anke; Mehta, Dolly; Malik, Asrar B (2016) ROS-activated calcium signaling mechanisms regulating endothelial barrier function. Cell Calcium 60:163-71
Tauseef, Mohammad; Farazuddin, Mohammad; Sukriti, Sukriti et al. (2016) Transient receptor potential channel 1 maintains adherens junction plasticity by suppressing sphingosine kinase 1 expression to induce endothelial hyperpermeability. FASEB J 30:102-10
Tran, Khiem A; Zhang, Xianming; Predescu, Dan et al. (2016) Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and Central Nervous System Homeostasis. Circulation 133:177-86
Yan, Zhibo; Wang, Zhen-Guo; Segev, Nava et al. (2016) Rab11a Mediates Vascular Endothelial-Cadherin Recycling and Controls Endothelial Barrier Function. Arterioscler Thromb Vasc Biol 36:339-49
Huang, Xiaojia; Dai, Zhiyu; Cai, Lei et al. (2016) Endothelial p110γPI3K Mediates Endothelial Regeneration and Vascular Repair After Inflammatory Vascular Injury. Circulation 133:1093-103
Mittal, Manish; Tiruppathi, Chinnaswamy; Nepal, Saroj et al. (2016) TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proc Natl Acad Sci U S A 113:E8151-E8158
Rajput, Charu; Tauseef, Mohammad; Farazuddin, Mohammad et al. (2016) MicroRNA-150 Suppression of Angiopoetin-2 Generation and Signaling Is Crucial for Resolving Vascular Injury. Arterioscler Thromb Vasc Biol 36:380-8
Dai, Zhiyu; Li, Ming; Wharton, John et al. (2016) Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2α. Circulation 133:2447-58
Weber, Evan W; Han, Fei; Tauseef, Mohammad et al. (2015) TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response. J Exp Med 212:1883-99
Baig, Mirza Saqib; Zaichick, Sofia V; Mao, Mao et al. (2015) NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1. J Exp Med 212:1725-38

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