Mfge8 and the Role of Apoptotic Cell Clearance in Lung Injury

描述(由申请人提供)： 这份提案概述了一项为期五年的职业发展计划，旨在为Atabai博士成为一名肺部医学学术内科科学家做好准备。Atabai博士感兴趣的是研究损伤和修复的潜在机制，特别是与肺相关的机制。急性肺损伤(ALL)是一种常见的破坏性炎症状态，可导致肺纤维化。尽管死亡率很高，但几乎没有有效的治疗方法，因为最近的证据表明细胞凋亡在人类ALI和肺纤维化中起致病作用。在他的导师迪恩·谢泼德博士的指导下，Atabai博士一直在研究MfgeS在肺损伤中的作用。MfgeS是一种整合素结合分子，有助于细胞凋亡的吞噬。Atabai博士发现，缺乏功能性MfgeS的小鼠在气管内注射博莱霉素后会出现夸大的肺纤维化。博莱霉素诱导上皮细胞凋亡、炎症和肺纤维化。Atabai博士的假设是，MfgeS通过促进凋亡细胞的清除来调节肺部的损伤和炎症。验证这一假说的具体目的是：1)确定MfgeS在肺细胞凋亡清除中的作用；2)确定MfgeS在调节炎症和肺损伤严重程度中的作用；3)确定磷脂酰丝氨酸残基在凋亡细胞中的作用以及在体内MfgeS介导的凋亡细胞清除中吞噬细胞上的AVP和av(35整合素)的作用。Atabai博士将使用成熟的体外和体内技术来实现这些目标，包括细胞培养、重组蛋白的产生、免疫组织化学、免疫细胞化学、DNA表达阵列、实时聚合酶链式反应、酶联免疫吸附试验和免疫印迹。Atabai博士的导师迪恩·谢泼德博士是一位多产且资金雄厚的科学家，在整合素生物学以及肺部炎症和纤维化方面拥有专业知识。谢泼德博士在培养成功的学术内科医生方面有着出色的记录。一个由备受尊敬的科学家组成的顾问小组将在获奖期间为阿塔巴伊博士提供进一步的指导。教学课程培训和参加地方和国家科学会议的详细计划将是该计划的最后组成部分。Atabai博士得到加州大学旧金山分校医学部和肺生物中心的全力支持，致力于事业发展和获得成功完成这项工作所需的所有资源。 (摘要结束)

DESCRIPTION (provided by applicant): This proposal outlines a five-year career development program designed to prepare Dr. Atabai for a career as an academic physician-scientist in pulmonary medicine. Dr. Atabai is interested in studying the mechanisms underlying injury and repair, particularly as they relate to the lung. Acute Lung Injury (All) is a common and devastating inflammatory condition that can lead to pulmonary fibrosis. Despite high mortality rates few effective therapies exist for ALL Recent evidence has implicated a pathogenic role for apoptosis in human ALI and pulmonary fibrosis. Under the guidance of his mentor, Dr. Dean Sheppard, Dr. Atabai has been examining the role of MfgeS, an integrin binding molecule that facilitates apoptotic cell engulfment, in lung injury. Dr. Atabai has found that mice lacking functional MfgeS develop exaggerated pulmonary fibrosis after intratracheal bleomycin administration. Bleomycin induces epithelial cell apoptosis, inflammation and pulmonary fibrosis. Dr. Atabai's hypothesis is that MfgeS modulates injury and inflammation in the lung by facilitating apoptotic cell clearance. The specific aims designed to test this hypothesis are 1) determining the role of MfgeS in apoptotic cell clearance in the lung, 2) determining the role of MfgeS in regulating inflammation and the severity of lung injury, 3) determining the role of phosphatidylserine residues on apoptotic cells and the avps and av(35 integrins on phagocytes in MfgeS-mediated apoptotic cell clearance in vivo. Dr. Atabai will use well-established in vitro and in vivo techniques to achieve these aims including cell culture, generation of recombinant proteins, immunohistochemistry, immunocytochemistry, DNA expression arrays, Real-Time PCR, ELISA, and immunoblotting. Dr. Atabai's mentor, Dr. Dean Sheppard, is a productive and well-funded scientist with expertise in integrin biology and inflammation and fibrosis in the lung. Dr. Sheppard has an outstanding track record of training successful academic physicians. An advisory panel of highly regarded scientists will provide further guidance to Dr. Atabai for the duration of the award. A detailed program of didactic course training and participation in local and national scientific conferences will be the final component of the program. Dr. Atabai has the full commitment of the UCSF Department of Medicine and the Lung Biology Center with regard to career development and access to all the resources necessary for the successful completion of this work. (End of Abstract)