Role of RAGE in Transfusion Mediated Acute Lung Injury

RAGE 在输血介导的急性肺损伤中的作用

• 批准号: 8048105
• 负责人: Nilam S. Mangalmurti
• 金额: $ 13.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048105
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; Advanced Glycosylation End Products; Advisory Committees; Age; Award; Biochemical; Blood Banks; Cardiac Surgery procedures; Cell Adhesion Molecules; Complication; Critical Care; Critical Illness; Data; Development; Endothelial Cells; Endotoxemia; Environment; Epidemiologic Studies; Erythrocyte Membrane; Erythrocyte Transfusion; Erythrocytes; Etiology; Fellowship; Functional disorder; Generations; Goals; Human; Hypersensitivity; In Vitro; Individual; Inflammatory; Kinetics; Knowledge; Laboratories; Lead; Lesion; Ligation; Lung; Lung Inflammation; Lung diseases; Lysine; Mediating; Medicine; Mentors; Morbidity - disease rate; Neutrophil Activation; Oxidative Stress; Patients; Pennsylvania; Population; Postdoctoral Fellow; Research; Risk; Role; Scientist; Supervision; Surface; System; Techniques; Training; Training Programs; Transfusion; Universities; career; clinically relevant; cytokine; defined contribution; glycation; in vivo; in vivo Model; insight; lectures; lung injury; mortality; mouse model; neutrophil; novel; oxidation; prevent; programs; public health relevance; receptor; receptor for advanced glycation endproducts

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for a career in investigative medicine in Pulmonary Diseases with the long term goal of establishing a research program within the field of acute lung injury. The applicant has finished a fellowship in Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh and is currently completing a research fellowship at the University of Pennsylvania. She is currently conducting research in transfusion-mediated acute lung injury, a common problem in the critically ill population. The research focus of this proposal is to elucidate some of the mechanisms by which stored erythrocytes induce lung injury during systemic inflammatory states. The central hypothesis of the proposal is that transfused RBC's directly "activate" pulmonary endothelial cells and neutrophils through the receptor for advanced glycation endproducts (RAGE) causing lung injury. In Specific Aim 1, the role of RAGE in endothelial cell activation induced by banked human RBCs will be defined. In Specific Aim 2, the effects of stored RBCs on neutrophil function in vitro and in vivo will be studied. In Specific Aim 3, the mechanisms by which stored RBCs induce lung injury during endotoxemia will be explored using mouse models. The training component of this proposal includes formal coursework, participation in a rich environment of post-doctoral lectures and seminars in lung diseases, acquisition of advanced laboratory techniques, and individual mentoring. This project will take place under the supervision of Dr. Steven Albelda who is the Director of Lung Research and Vice-chief of the Division of Pulmonary, Allergy and Critical Care Medicine at Penn. He has mentored over 60 trainees. In addition, an advisory committee of distinguished scientists will provide experimental assistance, intellectual guidance, and career advice throughout the duration of this award. PUBLIC HEALTH RELEVANCE: Recent epidemiological studies have shown that red cell transfusions are associated with the development of lung injury along with increased morbidity and mortality in the critically ill. The etiology underlying this association remains uncertain. The main goal of this study is to define the mechanism by which red blood cell transfusions induce lung injury in the critically ill. Knowledge derived from these studies may elucidate one mechanism underlying the consequences of red cell transfusion, provide new insight to a common problem in the critically ill, and hopefully lead to strategies to reduce this complication.

描述（由申请人提供）：该提案描述了一项为期5年的培训计划，用于肺部疾病的调查医学职业，其长期目标是在急性肺损伤领域建立研究计划。申请人已在匹兹堡大学完成肺部，过敏和重症监护医学研究金，目前正在宾夕法尼亚大学完成研究奖学金。她目前正在进行输血介导的急性肺损伤方面，这是重症患者的常见问题。该提案的研究重点是阐明在全身炎症状态下造成红细胞造成肺损伤的某些机制。该提案的中心假设是，输血的RBC直接通过受体进行了肺部内皮细胞和嗜中性粒细胞，从而导致肺部损伤，从而导致晚期糖基化终产物（RAGE）。在特定的目标1中，将定义愤怒在由人类RBC引起的内皮细胞激活中的作用。在特定的目标2中，将研究存储的RBC对体外和体内中性粒细胞功能的影响。在特定的目标3中，将使用小鼠模型探索储存的RBC在内毒素血症期间诱导肺损伤的机制。该提案的培训部分包括正式的课程，参与博士后讲座的丰富环境以及肺部疾病的研讨会，高级实验室技术的收购以及个人指导。该项目将在佩恩（Penn）肺部，肺，过敏和重症监护医学部的肺部研究主任史蒂文·阿尔贝尔达（Steven Albelda）的监督下进行。他指导了60多名学员。此外，杰出科学家的咨询委员会将在本奖项的整个期间提供实验帮助，智力指导和职业建议。 公共卫生相关性：最近的流行病学研究表明，红细胞输血与肺部损伤的发展以及危重疾病的发病率和死亡率增加有关。该关联的基础病因仍然不确定。这项研究的主要目的是定义红细胞输血诱导肺部损伤的机制。从这些研究中得出的知识可能阐明了红细胞输血后果的一种机制，为重病中的一个共同问题提供了新的见解，并希望导致减少这种并发症的策略。