Role of RAGE in Transfusion Mediated Acute Lung Injury

描述（由申请人提供）：该提案描述了一个为期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个研究计划。申请人已在匹兹堡大学完成肺部，过敏和重症监护医学的研究，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，这是危重患者的常见问题。本文的研究重点是阐明在全身炎症状态下储存的红细胞诱导肺损伤的一些机制。该建议的中心假设是，输血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Specific Aim 1中，RAGE在储存的人红细胞诱导的内皮细胞活化中的作用将被定义。在特异性目标2中，将研究储存红细胞对中性粒细胞功能的体外和体内影响。在Specific Aim 3中，我们将通过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。本建议的培训部分包括正式课程，参与丰富的博士后讲座和肺病研讨会，获得先进的实验室技术，以及个人指导。该项目将在肺研究主任兼宾夕法尼亚大学肺、过敏和重症医学部副主任Steven Albelda博士的监督下进行。他指导了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奖项期间提供实验协助、智力指导和职业建议。

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.