Dr. Dolly Mehta
Loss of lung vascular barrier leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which induces about 40% mortality. My research goal has been to identify the signaling “switches” that induce endothelial cell contraction leading to disruption of the endothelial barrier function and the signals that inactivate endothelial contraction and promote barrier repair using human endothelial cells and mice models such as genetically modified mice. Through series of several studies conducted over past funding cycles we have identified FAK to be a key “barrier protecting switch”. We showed that conditionally inducing loss of FAK in endothelium disrupted endothelial barrier function leading to increased lung vascular permeability and low grade inflammation. However, our preliminary data indicate that FAK is required for facilitating the effectiveness of stem cell therapy by shielding the synthesis of endothelial sphingosine 1 phosphate receptor 1 (S1PR1) from being repressed by epigenetic enzyme, DNA methyltransferase. Thus the center focus of the studies proposed in the current proposal will be to investigate the mechanism by which S1PR1 synthesis can be rescued in EC-FAK null mice to reinstate lung fluid homeostasis intrinsically and by stem cells. We believe these studies will potentially provide new approach to facilitate stem cell therapy in the setting of lung injury. To achieve the goals of Proposal, I have assembled a team of accomplished Co-Investigators who will provide their expertise in epigenetic regulation of S1PR1 downstream of FAK in endothelial cells and in promoting lung capillary barrier repair. I have significant experience in solving methodological problems and addressing scientific pitfalls. Moreover, I have published in high impact journals including J Exp Med, Circ Res, Blood, and JBC, an indication on my ability to successfully lead this important effort. Thus, I have both the expertise and the leadership skills necessary to carry out the studies proposed in this application.