IQGAP1 In Vascular Barrier Regulation During Acute Lung Injury

IQGAP1 在急性肺损伤期间血管屏障调节中的作用

• 批准号: 8351767
• 负责人: Mallar Bhattacharya
• 金额: $ 13.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8351767
• 关键词: Actins; Acute; Acute Lung Injury; Address; Agonist; Applications Grants; Award; Bacterial Pneumonia; Binding; Biological Assay; Biology; Blood Vessels; California; Cardiovascular system; Cell Line; Cell physiology; Cells; Cessation of life; Complex; Coupled; Critical Care; Cytoskeletal Modeling; Data; Endothelial Cells; Ensure; Extravasation; Faculty; Foundations; Functional disorder; Goals; Guanosine Triphosphate Phosphohydrolases; Human; IQ motif containing GTPase activating protein 1; In Vitro; Inflammation; Inflammatory Response; Integrin Binding; Integrins; Klebsiella; Klebsiella pneumonia bacterium; Knockout Mice; Knowledge; Laboratories; Ligation; Liquid substance; Lung; Mediating; Medicine; Mentors; Mentorship; Modeling; Mus; Oxygen; Peritoneal; Peritonitis; Physicians; Proteins; Pulmonary artery structure; Puncture procedure; Regulation; Research; Research Personnel; Research Proposals; Resources; Respiratory physiology; Role; San Francisco; Scaffolding Protein; Scientist; Signal Transduction; Sphingosine; Structure; Syndrome; Techniques; Testing; Time; Training; Training Programs; Trauma; Universities; Ventilator-induced lung injury; Wit; base; clinically relevant; design; electric impedance; in vivo; in vivo Model; instructor; lung injury; monolayer; mortality; mouse model; multidisciplinary; mutant; novel; prevent; professor; programs; protective effect; response; scaffold; skills; small hairpin RNA; sphingosine 1-phosphate; success; treatment effect

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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：这是 Mallar Bhattacharya 博士的 K08 奖项申请，他是加州大学旧金山分校 (UCSF) 医学系、肺科和重症监护科的讲师。 Bhattacharya 博士正在将自己定位为与急性肺损伤相关的血管生物学领域的年轻研究者。他与同事最近证明，整合素 β3 敲除小鼠在气管内注射 LPS 后肺血管渗漏增加。 Bhattacharya 博士随后鉴定了一种新型 β3 整合素结合伴侣 IQGAP1，并发现 IQGAP1 敲除小鼠在气管内注射 LPS 后肺血管渗漏也增加。此外，与α3基因敲除小鼠一样，IQGAP1基因敲除小鼠在腹膜滴注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 磷酸鞘氨醇处理后的屏障增强都是必需的，他也证明了对整合素 β3 的作用。这些初步数据引发了进一步表征 IQGAP1 和整合素 ?3 在血管渗漏中的作用所必需的几个问题：在内皮对多种激动剂的反应期间，IQGAP1 屏障是否具有保护作用，正如整合素 ?3 所证明的那样，以及这种屏障保护作用的细胞机制是什么（目标 1）？整合素是否能增强屏障？ 3 需要结合 IQGAP1（目标 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种微生物腹膜炎、克雷伯氏菌腹膜炎、克雷伯氏菌肺炎和呼吸机引起的肺损伤（目标 3）？围绕这些目标组织起来，并在正式的指导和课程的指导下，Bhattacharya 博士将追求以下目标：(1) 了解 IQGAP1 的屏障调节机制； （2）应用前沿知识和技术进行血管生物学研究； (3) 培养技能和专业知识，使他能够作为一名独立的医师科学家取得成功。 Bhattacharya 博士组建了一支 UCSF 教师多学科指导团队，由主要导师、医学教授 Dean Sheppard 和国际公认的整合素生物学专家组成；共同导师 Michael Matthay，医学教授，也是急性肺损伤方面多产的基础和转化研究员；共同导师肖恩·考夫林 (Shaun Coughlin)，心血管生物学和医学教授，血管生物学家先驱。 Bhattacharya 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，将使他能够开发必要的技能和初步数据 R01 拨款申请通过 IQGAP1 调节血管屏障。 公共卫生相关性：传染病和创伤与强烈的炎症反应有关，炎症反应会导致液体从血管渗漏到肺部空腔，称为肺损伤。血管内的细胞（称为内皮细胞）充当了防止这种渗漏的屏障，这种渗漏会阻碍肺功能并导致危险的低氧水平。目前的研究旨在了解肺内皮屏障调节的生物学，以揭示治疗急性肺损伤的潜在靶标。