Role of RAGE in Transfusion Mediated Acute Lung Injury

描述(由申请人提供)：本提案描述了一项为期5年的肺部疾病调查医学职业培训计划，其长期目标是在急性肺损伤领域建立一项研究计划。申请者已经在匹兹堡大学完成了肺、过敏和重症护理医学方面的奖学金，目前正在完成宾夕法尼亚大学的研究奖学金。她目前正在进行输血介导的急性肺损伤的研究，这是危重人群中的一个常见问题。这项建议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，输注的红细胞通过晚期糖基化终产物受体(RAGE)直接激活肺内皮细胞和中性粒细胞，导致肺损伤。在特定的目标1中，将确定RAGE在库人红细胞诱导的内皮细胞激活中的作用。在特定的目标2，将研究储存的红细胞在体外和体内对中性粒细胞功能的影响。在具体目标3中，将使用小鼠模型探讨储存的红细胞在内毒素血症中诱导肺损伤的机制。这项提议的培训部分包括正式的课程作业、参与丰富的肺病博士后讲座和研讨会环境、获取先进的实验室技术以及个人指导。该项目将在史蒂文·阿尔贝尔达博士的监督下进行，他是宾夕法尼亚大学肺部研究主任兼肺、过敏和重症监护医学部副主任。他已经指导了60多名实习生。此外，一个由杰出科学家组成的咨询委员会将在整个奖项期间提供实验援助、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，在危重病患者中，输注红细胞与肺损伤的发生以及发病率和死亡率的增加有关。这种联系背后的病因仍然不确定。本研究的主要目的是明确红细胞输注导致危重病人肺损伤的机制。从这些研究中获得的知识可能会阐明一种潜在的红细胞输注后果的机制，为危重患者的一个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.