Mfge8 and the Role of Apoptotic Cell Clearance in Lung Injury

Mfge8 和凋亡细胞清除在肺损伤中的作用

• 批准号: 7186033
• 负责人: KAMRAN ATABAI
• 金额: $ 12.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-08 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7186033
• 关键词: Acute Lung Injury; Address; Alveolar Macrophages; Animal Model; Apoptosis; Apoptotic; Architecture; Award; Binding; Biological Assay; Biology; Bleomycin; Cells; Condition; Cultured Cells; DNA; Data; Development; Disease; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Epithelial Cells; Excision; Fibrosis; Funding; Generations; Glycoproteins; Human; Immunoblotting; Immunohistochemistry; In Situ; In Vitro; Inflammation; Inflammatory; Inhibition of Apoptosis; Injury; Integrin Binding; Integrins; Knock-out; Laboratories; Lead; Lung; Mammary gland; Mediating; Medicine; Membrane; Mentors; Metabolic Clearance Rate; Modeling; Mus; Mutant Strains Mice; Numbers; Pb clearance; Peripheral Blood Lymphocyte; Phagocytes; Phosphatidylserines; Physicians; Placement; Play; Polymerase Chain Reaction; Process; Program Development; Pulmonary Fibrosis; Pulmonology; RGD (sequence); Range; Rate; Recombinant Proteins; Recombinants; Recovery; Research; Research Personnel; Resources; Rest; Role; Scientist; Severities; Signal Pathway; Signal Transduction; Specimen; Techniques; Testing; Therapeutic Intervention; Thinking; Time; Tissues; Training; Vascular Permeabilities; Work; Wound Healing; abstracting; alveolar epithelium; base; career; chemotherapeutic agent; cytokine; design; immunocytochemistry; in vivo; injured; injury and repair; insight; interest; lung injury; milk fat globule; mortality; mutant; null mutation; programs; response; restoration; symposium; uptake

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)

描述（由申请人提供）： 该提案概述了一个为期五年的职业发展计划，旨在帮助 Atabai 博士为肺科医学学术医师科学家的职业生涯做好准备。 Atabai 博士对研究损伤和修复的机制很感兴趣，特别是与肺部相关的机制。急性肺损伤（全部）是一种常见的破坏性炎症性疾病，可导致肺纤维化。尽管死亡率很高，但针对 ALL 的有效疗法却很少。最近的证据表明细胞凋亡在人类 ALI 和肺纤维化中具有致病作用。在导师 Dean Sheppard 博士的指导下，Atabai 博士一直在研究 MfgeS（一种促进凋亡细胞吞噬的整合素结合分子）在肺损伤中的作用。 Atabai 博士发现，缺乏功能性 MfgeS 的小鼠在气管内施用博莱霉素后会出现严重的肺纤维化。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 通过促进凋亡细胞清除来调节肺部损伤和炎症。测试这一假设的具体目的是 1) 确定 MfgeS 在肺部凋亡细胞清除中的作用，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肺损伤中的作用。凋亡细胞以及 MfgeS 介导的体内凋亡细胞清除中吞噬细胞上的 avps 和 av(35 整合素)。Atabai 博士将使用实现这些目标的完善的体外和体内技术包括细胞培养、重组蛋白的生成、免疫组织化学、免疫细胞化学、DNA 表达阵列、实时 PCR、ELISA 和免疫印迹。Atabai 博士的导师 Dean Sheppard 博士，谢泼德博士是一位多产、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丰富的专业知识，在培训成功的学术医生方面拥有出色的记录。在获奖期间为阿塔拜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 UCSF 医学系和肺生物学中心在职业发展方面的充分承诺，并获得成功完成这项工作所需的所有资源。 （摘要完）