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

基本信息

批准号：
8240473
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
项目类别：
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/8240473
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

项目摘要

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 年的肺部疾病研究医学职业培训计划，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了肺、过敏和重症监护医学方面的奖学金，目前正在宾夕法尼亚大学完成研究奖学金。她目前正在研究输血介导的急性肺损伤，这是危重病人中的一个常见问题。该提案的研究重点是阐明在全身炎症状态下储存的红细胞诱发肺损伤的一些机制。该提案的中心假设是，输注的红细胞通过晚期糖基化终末产物（RAGE）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 RAGE 在储存的人类红细胞诱导的内皮细胞活化中的作用。在具体目标 2 中，将研究储存的红细胞对体外和体内中性粒细胞功能的影响。在具体目标 3 中，将使用小鼠模型探讨储存的红细胞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以及个人指导。该项目将在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 Steven Albelda 博士的监督下进行。他指导过60多名学员。此外，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，红细胞输注与肺损伤的发生以及危重病患者发病率和死亡率的增加有关。这种关联的病因学仍不确定。这项研究的主要目标是确定红细胞输注引起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红细胞输注后果的一种机制，为危重病患者的常见问题提供新的见解，并有望找到减少这种并发症的策略。