IQGAP1 In Vascular Barrier Regulation During Acute Lung Injury

描述（由申请人提供）：这是一份申请K08奖的申请书，申请对象是加州大学旧金山分校（UCSF）肺科和重症监护室医学系讲师Mallar Bhattacharya博士。巴塔查里亚博士正在建立自己作为一个年轻的研究者在血管生物学领域与急性肺损伤。他最近与同事一起证明了整合素？3基因敲除小鼠经气管内LPS后肺血管渗漏增加。巴塔查里亚博士随后发现了一本小说？3整合素结合伙伴IQGAP1，并发现IQGAP1敲除小鼠在气管内LPS后肺血管泄漏也增加。此外，比如？3敲除小鼠，IQGAP1敲除小鼠腹腔注射LPS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13磷酸鞘氨醇治疗后的屏障增强都是必需的，他已经证明了整合素的作用。3也一样。这些初步数据激发了对进一步表征IQGAP1和整合素的作用所必需的几个问题。在血管泄漏中：IQGAP1屏障在多种激动剂的内皮反应中是否具有保护作用，正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）？整合素能增强屏障吗？3需要结合IQGAP1 (Aim 2)？IQGAP1在临床相关的体内模型中是否具有类似的屏障保护功能，包括盲肠结扎和穿刺引起的多微生物腹膜炎、克雷伯菌腹膜炎、克雷伯菌肺炎和呼吸机诱导的肺损伤（Aim 3）？围绕这些目标，在正式指导和课程的指导下，Bhattacharya博士将追求以下目标：(1)了解IQGAP1的障碍调节机制；(2)运用前沿知识和技术研究血管生物学；(3)培养技能和专业知识，使他能够作为一名独立的内科科学家取得成功。Bhattacharya博士组建了一个由UCSF教师组成的多学科指导团队，其中包括主要导师Dean Sheppard，医学教授和国际公认的整合素生物学专家；共同导师Michael Matthay，医学教授和急性肺损伤的多产基础和转化研究人员；和共同导师肖恩·考夫林，心血管生物学和医学教授和先驱血管生物学家。巴塔查里亚博士的研究计划侧重于新型蛋白质IQGAP1，加上他的结构化培训计划，将使他能够培养必要的技能和初步数据

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.