Increased lung vascular endothelial permeability leads to the leakage of fluid and plasma proteins into lung tissue, a primary factor in the pathogenesis of Acute Lung Injury (ALI). Our studies 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 activation is required and sufficient for endothelial contraction that mediates increased lung vascular permeability. The proposed studies will use the agonist thrombin, which activates protease activating receptor (PAR-1) on the endothelial cell surface and produces diacylglycerol, the direct activator of the TRPC6 channel. Studies will determine the role of dual lipid/protein phosphatase PTEN in the mechanism of TRPC6 activation. We will address the role of TRPC6-mediated increase in intracellular Ca2+ as a requirement for signaling the activation of RhoA and MLCK-L, and thereby promoting endothelial cell contraction.
Our Specific Aims are to determine 1) role of endothelial ROC, TRPC6 in mediating Ca2+ signaling dependent increases in lung microvascular permeability, 2) PTEN-mediated mechanism of activation of TRPC6 and its consequences in the regulation of endothelial barrier function, and 3) downstream signaling mechanisms of TRPC6-induced increase in lung endothelial permeability involving the activation of PKCa and p60Src kinase and the effectors RhoA and MLCK-L isoform. These studies will be carried out at multiple levels including utilizing endothelial cells and lungs from mice carrying deletions in specific genes. Our hope is that the proposal will provide novel insights into the development of therapeutic strategies directed against TRPC6 that will prevent lung vascular """"""""leakiness"""""""".
The semi-selective endothelial cell monolayer partitions blood and tissue components. Increased permeability of this monolayer leads to leakage of fluid and macromolecules into lung tissue from the blood stream. If this leakage is not stopped it will lead to lung injury. Currently, there are no effective treatments for this problem. We believe that characterization of an important calcium channel in endothelial cells, TRPC6 will provide valuable insights to help us develop therapeutic strategies to reverse the vascular leakiness and thereby lung injury.
|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|
|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|
|Fernandez, Ruby A; Wan, Jun; Song, Shanshan et al. (2015) Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype. Am J Physiol Cell Physiol 308:C581-93|
|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|
|Smith, Kimberly A; Voiriot, Guillaume; Tang, Haiyang et al. (2015) Notch Activation of Ca(2+) Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension. Am J Respir Cell Mol Biol 53:355-67|
|Rajasekaran, Subbiah; Tamatam, Chandramohan R; Potteti, Haranatha R et al. (2015) Visualization of Fra-1/AP-1 activation during LPS-induced inflammatory lung injury using fluorescence optical imaging. Am J Physiol Lung Cell Mol Physiol 309:L414-24|
|Beckers, Cora M L; Knezevic, Nebojsa; Valent, Erik T et al. (2015) ROCK2 primes the endothelium for vascular hyperpermeability responses by raising baseline junctional tension. Vascul Pharmacol 70:45-54|
|Chavez, Alejandra; Schmidt, Tracy Thennes; Yazbeck, Pascal et al. (2015) S1PR1 Tyr143 phosphorylation downregulates endothelial cell surface S1PR1 expression and responsiveness. J Cell Sci 128:878-87|
|Mehta, Dolly; Ravindran, Krishnan; Kuebler, Wolfgang M (2014) Novel regulators of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol 307:L924-35|
|Sukriti, Sukriti; Tauseef, Mohammad; Yazbeck, Pascal et al. (2014) Mechanisms regulating endothelial permeability. Pulm Circ 4:535-51|
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