This is an application for a K08 award for Dr. Mallar Bhattacharya, an Instructor in the Department of Medicine, Division of Pulmonary and Critical Care, at the University of California, San Francisco (UCSF). Dr. Bhattacharya is establishing himself as a young investigator in the field of vascular biology relating to acute lung injury. Wit colleagues he has recently demonstrated that integrin ?3 knockout mice have increased pulmonary vascular leak after intratracheal LPS. Dr. Bhattacharya has subsequently identified a novel ?3 integrin binding partner, IQGAP1, and has found that IQGAP1 knockout mice also have increased pulmonary vascular leak after intratracheal LPS. Furthermore, like ?3 knockout mice, IQGAP1 knockout mice have increased mortality after peritoneal instillation of LPS. Finally, in endothelial monolayer, IQGAP1 is necessary both for cortical actin formation and barrier enhancement after sphingosine 13phosphate treatment, effects that he has demonstrated for integrin ?3 as well. These preliminary data motivate several questions that are necessary for further characterization of the role of IQGAP1 and integrin ?3 in vascular leak: is IQGAP1 barrier protective during endothelial responses to multiple agonists, as has been demonstrated for integrin ?3, and what is the cellular mechanism of this barrier protective effect (Aim 1)? Does barrier enhancement by integrin ? 3 require binding of IQGAP1 (Aim 2)? Does IQGAP1 have a similar barrier protective function in clinically relevant in vivo models, including polymicrobial peritonitis due to cecal ligation and puncture, Klebsiella peritonitis, Klebsiella pneumonia, and ventilator induced lung injury (Aim 3)? Organized around these aims and guided by both formal mentorship and coursework, Dr. Bhattacharya will pursue the following goals: (1) to understand the mechanism of barrier regulation by IQGAP1;(2) to apply cutting edge knowledge and techniques in the study of vascular biology;and (3) to develop skills and expertise that will enable him to achieve success as an independent physician scientist. Dr. Bhattacharya has assembled a multidisciplinary mentoring team of UCSF faculty composed of primary mentor Dean Sheppard, Professor of Medicine and an internationally recognized expert in integrin biology;co-mentor Michael Matthay, Professor of Medicine and a prolific basic and translational researcher in acute lung injury;and co-mentor Shaun Coughlin, Professor of Cardiovascular Biology and Medicine and a pioneer vascular biologist. Dr. Bhattacharya's research proposal focusing on the novel protein IQGAP1 coupled with his structured training plan will allow him to develop the necessary skills and preliminary data for an R01 grant application on vascular barrier regulation by IQGAP1.
Infectious illnesses and trauma are associated with an exuberant inflammatory response that leads to leak of fluid from blood vessels into the lung's airspaces, known as lung injury. The cells that line the blood vessels, called endothelial cells, act as a barrier against this leakage, which impedes lung function and causes dangerously low levels of oxygen. The current research seeks to understand the biology of regulation of the lung endothelial barrier in order to reveal potential targets for the treatment of acute lung injury.