Role of RAGE and Necroptosis in Transfusion Mediated Lung Inflammation

RAGE 和坏死性凋亡在输血介导的肺部炎症中的作用

基本信息

批准号：
9195143
负责人：
Nilam S. Mangalmurti
金额：
$ 40.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195143
关键词：
Adult Respiratory Distress Syndrome Animal Model Apoptosis Binding Caspase Cell Death Cell Nucleus Cessation of life Complication Critical Illness Data Development Endothelial Cells Engineering Erythrocyte Transfusion Erythrocytes Etiology Exposure to Goals HMGB1 Protein Human Immune response In Vitro Inflammatory Inflammatory Response Injury Ischemic Brain Injury Knockout Mice Knowledge Lead Life Ligands Lung Lung Inflammation Lung diseases Mediating Mediator of activation protein Mitochondrial DNA Modeling Molecular Morbidity - disease rate Myocardial Infarction Necrosis Nuclear Translocation Nucleic Acid Binding Nucleic Acids Operative Surgical Procedures Pathogenesis Pathway interactions Patients Pattern Pattern recognition receptor Predisposition Protein Kinase Publishing RIPK3 gene Risk Role Savings Stimulus System TNF gene Transfusion Trauma patient Vascular Diseases cell injury clinically relevant endothelial dysfunction epidemiology study immunoregulation in vivo in vivo Model lung injury mortality novel novel therapeutics prevent public health relevance receptor receptor for advanced glycation endproducts response

项目摘要

DESCRIPTION (provided by applicant): Recent epidemiologic studies have demonstrated increased morbidity, mortality, and the development of Acute Respiratory Distress Syndrome (ARDS) associated with red blood cell (RBC) transfusions in the critically ill, yet the mechanisms underlying this association remain unknown. Our data demonstrate that banked RBCs induce necroptosis (a form of regulated necrotic cell death) of lung endothelial cells and enhance susceptibility to subsequent injury. We have previously demonstrated that the proinflammatory receptor for advanced glycation endproducts (RAGE) mediates lung endothelial dysfunction following RBC transfusion. The overall goal of this proposal is to elucidate the role of RAGE in RBC-induced necroptosis. In Specific Aim 1 the role of RAGE in sensing necroptotic stimuli will be examined in vitro and in a micro-engineered model of human lung. Specific Aim 2 will explore the role of intracellular RAGE in necroptosis execution. Lastly, Specific Aim 3 will examine the in vivo effects of RBC- induced necroptosis on lung injury using animal models. Knowledge derived from these studies will elucidate some of the mechanisms by which RBCs enhance susceptibility to lung injury and hopefully lead to novel therapies to prevent the morbidity associated with RBC transfusions.

描述（由申请人提供）：最近的流行病学研究表明，重症患者的发病率、死亡率和急性呼吸窘迫综合征（ARDS）的发病率增加与红细胞（RBC）输注有关，但这种关联的机制仍不清楚我们的数据表明，储存的红细胞会诱导肺内皮细胞坏死性凋亡（一种受调节的坏死性细胞死亡），并增加对随后损伤的易感性。先前已证明晚期糖基化终产物促炎受体 (RAGE) 介导红细胞输注后的肺内皮功能障碍。本提案的总体目标是阐明 RAGE 在红细胞诱导的坏死性凋亡中的作用。传感坏死性凋亡刺激将在体外和人肺微工程模型中进行检查，具体目标 2 将探讨细胞内 RAGE 在坏死性凋亡中的作用。最后，具体目标 3 将使用动物模型检查红细胞诱导的坏死性凋亡对肺损伤的体内影响，这些研究中获得的知识将阐明红细胞增强肺损伤易感性的一些机制，并有望带来新的治疗方法。预防与红细胞输注相关的发病率。