Studies proposed in Project 3 will investigate the fundamental question that Ca2+ entry mediated by transient receptor potential cation channel 6 (TRPC6), a receptor-operated channel (ROC), is a critical determinant of increased endothelial permeability. We will test the hypothesis that TRPC6 is the critical influx pathway for Ca2+ that triggers the activation of endothelial contractile mechanisms RhoA and endothelial isoform of MLCK (EC-MLCK). If this hypothesis is correct, it would demonstrate a fundamental link between TRPC6 and the RhoA-EC-MLCK pathway. We also postulate based on our Supporting Data a potentially important relationship by which TRPC6-activated signaling upregulates the activity of TRPC1, a store-operated channel (SOC). Thus, our concept is that TRPC6 by activating both RhoA and EC-MLCK controls the state of endothelial contraction and additionally that TRPC6 activates signals that upregulate TRPC1 activity, thereby protracting and/or amplifying the endothelial permeability response.
Our Specific Aims are to determine: 1) the role of the endothelial ROC, TRPC6, interaction with the SOC, TRPC1, in mediating Ca2+ signaling-dependent increase in lung vascular permeability;2) the role of TRPC6-activated signaling in mediafing RhoA and ECMLCK activation and the requirement of these effectors in mediating increased lung vascular endothelial permeability and 3) the role of EC-MLCK downstream of TRPC6 in upregulating TRPC1 activity, and its consequences in increasing lung endothelial permeability. These studies will be carried out utilizing endothelial cells and lungs from mice carrying deletions of specific genes. We believe that the studies will provide a new understanding of the Ca2+-mediated increase in lung vascular permeability and edema formation. These new findings will help to unravel the details of how the interactions between TRPC6 and TRPC1 signals the Ca2+-dependent increase in lung endothelial permeability. The studies are expected to offer a novel therapeutic strategy for inhibiting TRPC6 and TRPC1 activities, thereby abrogating or reversing lung vascular leakiness.

Public Health Relevance

A rise in intracellular calcium by activating cell contraction leads to formation of pores between endothelial cells through which blood proteins can gain access to interstitium and impair gas exchange in lungs thereby leading to acute lung injury (ALI). We believe proposed studies will provide novel insights into the role of a calcium cahnnel TRPC6 in inducing ALI and will identify TRPC6 as a therapeutic target to prevent ALI.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL060678-14
Application #
8620692
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$653,721
Indirect Cost
$237,338
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Liu, Yuru; Kumar, Varsha Suresh; Zhang, Wei et al. (2015) Activation of type II cells into regenerative stem cell antigen-1(+) cells during alveolar repair. Am J Respir Cell Mol Biol 53:113-24
Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R et al. (2015) Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308:L208-20
Piegeler, Tobias; Dull, Randal O; Hu, Guochang et al. (2014) Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling. BMC Anesthesiol 14:57
Mao, Mao; Varadarajan, Sudhahar; Fukai, Tohru et al. (2014) Nitroglycerin tolerance in caveolin-1 deficient mice. PLoS One 9:e104101
Chernaya, Olga; Shinin, Vasily; Liu, Yuru et al. (2014) Behavioral heterogeneity of adult mouse lung epithelial progenitor cells. Stem Cells Dev 23:2744-57
Thangavel, Jayakumar; Malik, Asrar B; Elias, Harold K et al. (2014) Combinatorial therapy with acetylation and methylation modifiers attenuates lung vascular hyperpermeability in endotoxemia-induced mouse inflammatory lung injury. Am J Pathol 184:2237-49
Tobin, Matthew K; Bonds, Jacqueline A; Minshall, Richard D et al. (2014) Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab 34:1573-84
Yang, Kai-Chien; Rutledge, Cody A; Mao, Mao et al. (2014) Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase. Circ Arrhythm Electrophysiol 7:701-10
Mehta, Dolly; Ravindran, Krishnan; Kuebler, Wolfgang M (2014) Novel regulators of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol 307:L924-35
Mittal, Manish; Siddiqui, Mohammad Rizwan; Tran, Khiem et al. (2014) Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20:1126-67

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