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: 7327793
• 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/7327793
• 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; 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; uptake

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 conferenceswill 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.

该提案概述了一项为期五年的职业发展计划，旨在为Atabai博士准备职业 作为肺医学的学术医师科学家。 Atabai博士有兴趣研究 损伤和修复的机制，尤其是与肺有关的机制。急性肺损伤（全部）是 常见且毁灭性的炎症状况，可能导致肺纤维化。尽管死亡率很高 对于所有最近证据的率很少有有效疗法，这暗示了凋亡在 人ALI和肺纤维化。在他的导师Dean Sheppard博士的指导下，Atabai博士 一直在研究MFGE的作用，MFGE是一种促进凋亡细胞吞噬的整合素结合分子 肺部受伤。 Atabai博士发现，缺乏功能性MFGE的小鼠会出现夸张的肺纤维化 气管内博来霉素给药后。博来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调节肺部的损伤和炎症 促进凋亡细胞清除率。旨在检验此假设的具体目的是1）确定 MFGE在肺中凋亡细胞清除率中的作用，2）确定MFGE在调节中的作用 炎症和肺损伤的严重程度，3）确定磷脂酰丝氨酸残基在 凋亡细胞以及AVP和AV（在MFGES介导的凋亡细胞清除中的吞噬细胞上的35个整合素 体内。 Atabai博士将使用良好的体外和体内技术来实现这些目标在内 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PCR，ELISA和免疫印迹。 Atabai博士的导师Dean Sheppard博士是 在整合素生物学和炎症和纤维化方面具有专业知识的生产性且资金充足的科学家 肺。 Sheppard博士在培训成功的学术医师方面拥有出色的记录。咨询 备受推崇的科学家小组将在奖项期间为Atabai博士提供进一步的指导。一个 教学课程培训和参与本地和国家科学会议的详细计划将会 成为程序的最终组成部分。 Atabai博士拥有UCSF部门的全部承诺 医学和肺生物学中心关于职业发展和获得所有资源 成功完成这项工作所必需的。