IQGAP1 In Vascular Barrier Regulation During Acute Lung Injury

描述（由申请人提供）：这是一份K 08奖的申请，申请人是加州大学弗朗西斯科分校（UCSF）医学系肺和重症监护科的讲师Mallar Bhattacharya博士。Bhattacharya博士正在确立自己作为与急性肺损伤相关的血管生物学领域的年轻研究者的地位。他的同事最近证明了整合素？3只基因敲除小鼠在经气管内注射LPS后肺血管渗漏增加。巴塔查亚博士后来发现了一本小说？3整联蛋白结合伴侣IQGAP 1的研究，并发现IQGAP 1敲除小鼠在经皮内治疗LPS后也具有增加的肺血管渗漏。此外，像？3基因敲除小鼠中，IQGAP 1基因敲除小鼠腹腔滴注LPS后死亡率增加。最后，在内皮细胞单层，IQGAP 1是必要的皮质肌动蛋白的形成和屏障增强鞘氨醇13磷酸治疗后，他已经证明了整合素？3也是。这些初步的数据激发了几个问题，是必要的IQGAP 1和整合素的作用进一步表征？3在血管渗漏中：IQGAP 1屏障在内皮对多种激动剂的反应中是否具有保护作用，如整合素所证明的那样？3，这种屏障保护作用的细胞机制是什么（目的1）？通过整合素增强屏障吗？3需要IQGAP 1的约束力（目标2）？IQGAP 1在临床相关体内模型中是否具有相似的屏障保护功能，包括盲肠结扎和穿刺引起的多微生物腹膜炎、克雷伯氏菌腹膜炎、克雷伯氏菌肺炎和呼吸机诱导的肺损伤（目的3）？Bhattacharya博士将追求以下目标：（1）了解IQGAP 1的屏障调节机制;（2）在血管生物学研究中应用前沿知识和技术;（3）发展技能和专业知识，使他能够作为独立的医生科学家取得成功。Bhattacharya博士组建了一个由主要导师Dean Sheppard，医学教授和国际公认的整合素生物学专家组成的UCSF教师多学科指导团队;共同导师Michael Matthay，医学教授和多产的急性肺损伤基础和转化研究人员;和共同导师Shaun Coughlin，心血管生物学和医学教授和先锋血管生物学家。Bhattacharya博士的研究计划侧重于新蛋白质IQGAP 1，加上他的结构化培训计划，将使他能够发展必要的技能和初步数据， R 01资助申请IQGAP 1对血管屏障的调节。

DESCRIPTION (provided by applicant): 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.