Acute lung injury (ALI) is a devastating, often fatal, inflammatory lung disease that usually occurs in conjunction with a catastrophic medical condition, such as pneumonia, shock, sepsis, and trauma. No specific therapies currently exist for ALI. Because the vast surface area of the pulmonary microvasculature intimately associates with gas-exchanging alveolar units, the integrity of the endothelial exchange barrier is a key factor in lung homeostasis and normal cardiovascular function. Increased endothelial permeability in lungs leads to the leakage of fluid and macromolecules, and if not resolved, to ALI. Homeostasis of endothelial barrier function requires dynamic interactions of a complex array of proteins that connects adherens junctions with cell-matrix adhesions. Thus, overall goal of my lab has been to identify the signaling "switches" (i) that induce endothelial cell contraction and compromise endothelial barrier function, and (ii) those that turn off endothelial contraction, promoting barrier repair.

Specific Projects in the lab include:

1. Investigate the role of transient receptor potential channel (TRPC) primarily TRPC6 and TRPC1, which mediates Ca2+ entry in endothelial cells, in inducing cytosketal re-organization and subsequently the loss of endothelial barrier function. In this project we seek to identify the mechanism(s) by which inflammatory mediators such as thrombin, a pro-coagulant protease, and endotoxin LPS activate TRP channel activity and whether TRPC activation is linked with the activation of RhoGTPases consequently inducing ALI.


2. Determine the role of GDI-1 phosphorylation at Ser96 in regulating RhoA activity and the integrity of endothelium. Based on our recent finding that phosphorylation of GDI-1 at Ser96 phosphorylation specifically activate RhoA activity studies focused in this project will use structural biology approaches to develop a GDI-1 small molecule inhibitor that will prevent RhoA signaling and thereby endothelial contractility.



S1P via Rac1 forms inter-endothelial junctions.



3. Address the novel role of focal adhesion kinase (FAK) in turning-off endothelial cell contraction, thereby restoring endothelial barrier. In this project we will investigate the role of FAK -mediated activation of p190RhoGAP and N-WASP activities in inactivating RhoA and inducing re-assembly of adherens junctions and focal adhesions.


4. Determine that sphingosine kinase 1 (SPHK1) is a potential key regulatory switch that antagonizes thrombin-induced increase in endothelial permeability. S1P is a potent barrier enhancing agonist. S1P is synthesized by sphingosine kinase. We will assess that SPHK1-mediated intracellular S1P signaling is required for restoring endothelial barrier.

We use genetic mouse models and deliver mutant constructs or siRNA to down regulate identified genes in endothelial cells and mouse lungs to assess the role of above described signaling switches in regulating endothelial barrier function. These studies are accompanied with state-of-the-art cell imaging techniques. We hope that undertaken projects will be potentially helpful in developing anti-ALI drugs.

Lab Members

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