Role of RAGE in Transfusion Mediated Acute Lung Injury

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于肺部疾病研究医学的职业生涯，长期目标是在急性肺损伤领域建立研究计划。申请人已经完成了匹兹堡大学的肺，过敏和重症监护医学奖学金，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的研究，这是危重人群中的常见问题。本提案的研究重点是阐明储存的红细胞在全身炎症状态下诱导肺损伤的一些机制。该提案的中心假设是，输注的RBC通过晚期糖基化终末产物（AGEs）受体直接“激活”肺内皮细胞和中性粒细胞，导致肺损伤。在具体目标1中，将定义BMPs在库存人RBC诱导的内皮细胞活化中的作用。在特定目标2中，将研究储存的RBC对体外和体内中性粒细胞功能的影响。在具体目标3中，将使用小鼠模型探索内毒素血症期间储存的RBC诱导肺损伤的机制。该提案的培训部分包括正式的课程，参与肺病博士后讲座和研讨会的丰富环境，获得先进的实验室技术和个人指导。该项目将在Steven Albelda博士的监督下进行，Steven Albelda博士是宾夕法尼亚大学肺部研究主任兼肺部，过敏和重症监护医学部副主任。他已经指导了60多名学员。此外，一个由杰出科学家组成的咨询委员会将在整个颁奖期间提供实验援助，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，红细胞输注与肺损伤的发生有关，沿着危重病患者发病率和死亡率的增加。这种相关性的病因仍不确定。本研究的主要目的是确定红细胞输注诱导危重患者肺损伤的机制。从这些研究中获得的知识可能阐明红细胞输注后果的一种机制，为危重患者的常见问题提供新的见解，并有望导致减少这种并发症的策略。

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.