IQGAP1 In Vascular Barrier Regulation During Acute Lung Injury

描述(申请人提供)：这是一份K08奖项的申请书，授予Mallar Bhattacharya博士，他是加州大学旧金山分校(UCSF)肺和重症监护科医学部的讲师。巴塔查里亚博士在与急性肺损伤相关的血管生物学领域确立了自己作为一名年轻研究员的地位。他最近与同事一起证明，整合素基因敲除的小鼠在气管内注射脂多糖后会增加肺血管渗漏。Bhattacharya博士随后发现了一种新的整合素结合伙伴IQGAP1，并发现IQGAP1基因敲除小鼠在气管内脂多糖后也增加了肺血管渗漏。此外，与？3基因敲除小鼠一样，IQGAP1基因敲除小鼠在腹腔注射脂多糖后死亡率增加。最后，在内皮单层中，IQGAP1对于皮质肌动蛋白的形成和鞘氨醇13磷酸处理后屏障的增强都是必需的，他也展示了对整合素？3的作用。这些初步数据引发了几个问题，这些问题对于进一步描述IQGAP1和整合素？3在血管泄漏中的作用是必要的：在内皮细胞对多种激动剂的反应中，IQGAP1屏障是否具有保护作用，就像整合素？3已经证明的那样，这种屏障保护作用的细胞机制是什么(目标1)？整合素？3是否需要结合IQGAP1(目标2)？IQGAP1在临床相关的活体模型中是否具有类似的屏障保护功能，包括盲肠结扎和穿孔引起的多菌腹膜炎、克雷伯氏菌腹膜炎、肺炎克雷伯菌和呼吸机诱导的肺损伤(目标3)？Bhattacharya博士围绕这些目标组织，在正式指导和课程指导下，将追求以下目标：(1)了解IQGAP1的屏障调节机制；(2)将尖端知识和技术应用于血管生物学研究；(3)发展技能和专业知识，使他能够作为一名独立的内科科学家取得成功。Bhattacharya博士组建了加州大学旧金山分校的多学科导师团队，成员包括：主要导师、医学教授、国际公认的整合素生物学专家Dean Seppard；共同导师、医学教授、多产的急性肺损伤基础研究和翻译研究员Michael Matthay；以及共同导师、心血管生物学和医学教授、先驱血管生物学家Shaun Coughlin。Bhattacharya博士专注于新型蛋白质IQGAP1的研究提案，加上他的结构化训练计划，将使他能够发展必要的技能和初步数据 R01关于IQGAP1调节血管屏障的申请。

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.