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The Complement System and Ischemic Acute Renal Failure

补体系统与缺血性急性肾衰竭

基本信息

批准号：
8105421
负责人：
Joshua M Thurman
金额：
$ 30.54万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8105421
关键词：
Acute Kidney Failure Aftercare Age related macular degeneration Agonist Alternative Complement Pathway Annexins Antibodies Apoptosis Binding Biological Assay Bypass C3bi Cell Surface Receptors Cell surface Cells Chemicals Complement Complement 3a Complement 3b Complement 3b Inactivators Complement 3d Receptors Complement 5a Complement Activation Complement Factor B Complement Factor H Complement Inactivators Complement Receptor Complex Crying Cytolysis Data Deposition Development Disease Dominant-Negative Mutation Endogenous Factors Enzyme-Linked Immunosorbent Assay Enzymes Epithelial Cells Gene Proteins Generations Grant Health Hemolytic-Uremic Syndrome Histologic Human Hypoxia Immunofluorescence Immunologic Immunofluorescence Microscopy In Vitro Incubated Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intensive Care Units Ischemia Kidney Laboratories Measurement Measures Mediating Mediator of activation protein Methods Mus Neutrophil Infiltration Pathologist Pathway interactions Phenotype Plasma Plasminogen Production Proteins Publishing Recovery Regulation Reperfusion Therapy Role Serum Signal Transduction Site Surface System TLR2 gene TLR4 gene Testing Therapeutic Agents Thromboplastin Time Tissues Toll-like receptors Transfection Treatment Efficacy Tubular formation Urea Nitrogen Western Blotting Work cell injury chemokine complement system cytotoxic cytotoxicity in vitro Model in vivo in vivo Model inhibitor/antagonist keratinocyte macrophage inflammatory protein 2 mortality novel novel therapeutics pathogen prevent protein expression receptor reconstitution renal ischemia research study response sample fixation

项目摘要

DESCRIPTION (provided by applicant): This grant examines the role of the complement system in the development of ischemic acute renal failure. Our published work demonstrates that complement activation contributes to renal injury after ischemia/reperfusion (I/R), and that activation occurs primarily through the alternative pathway. The alternative pathway has emerged, in recent years, as a critical mediator of injury in a number of different diseases. This system is effective at rapidly eliminating invasive pathogens, but insufficient control of the activating enzymes permits inflammatory injury of host cells. The primary hypothesis of this grant is that hypoxia alters the surface expression of complement inhibitory proteins by proximal tubular epithelial cells. This changes the cells from a complement inhibitory to a complement activating phenotype. Once activated, the alternative pathway triggers generation of pro-inflammatory signals, including C3a, C5a, macrophage inflammatory protein-2 (MIP-2) and keratinocyte derived chemokine (KC). To test this hypothesis we will use in vivo and in vitro models to determine whether the loss of surface inhibition is sufficient to cause spontaneous alternative pathway activation, and the mechanisms by which this surface inhibition is lost after I/R (SA1). Factor H is a potent alternative pathway inhibitor that circulates in high concentrations but fails to prevent alternative pathway mediated injury in certain diseases. We will also examine whether a novel complement inhibitor that targets factor H to the site of complement activation prevents pathological complement activation after renal I/R, and the factors that modulate protection of this surface by endogenous factor H (SA2). Finally, we will examine the mechanisms by which alternative pathway activation in the tubulointerstitium triggers a widespread inflammatory response (SA3). Ischemic acute renal failure is one of the most common causes of acute renal failure, and is associated with a mortality rate of greater than 50% in the intensive care unit setting. A number of complement inhibitors have become available, including a specific inhibitor of the alternative pathway that has been developed by our laboratory and a targeted inhibitor of the alternative pathway that was developed by one of our collaborators. The proposed studies should help delineate the benefits and limitations of complement inhibition as a therapy for ischemic acute renal failure, as well as expand our understanding of complement activation as a mediator of inflammation after renal tubular injury. PUBLIC HEALTH RELEVANCE Ischemic acute renal failure is one of the most common causes of acute renal failure, and is associated with a mortality rate of greater than 50% in the intensive care unit setting. Studies have demonstrated that the complement system is activated within the kidney after ischemia. The proposed experiments examine the complex interactions between the complement system and the kidney. These studies will identify therapies that effectively inhibit the complement system and determine whether these agents will ameliorate ischemic acute renal failure.

描述（由申请人提供）：该基金审查补体系统在缺血性急性肾衰竭发展中的作用。我们已发表的工作表明，补体激活有助于缺血/再灌注（I/R）后的肾损伤，激活主要通过旁路途径发生。近年来，替代途径已成为许多不同疾病中损伤的关键介质。该系统在快速消除侵入性病原体方面是有效的，但是对活化酶的控制不足允许宿主细胞的炎性损伤。这项研究的主要假设是缺氧改变了近端肾小管上皮细胞补体抑制蛋白的表面表达。这将细胞从补体抑制表型改变为补体激活表型。一旦激活，旁路途径触发促炎信号的产生，包括C3 a、C5 a、巨噬细胞炎性蛋白-2（MIP-2）和角质形成细胞衍生的趋化因子（KC）。为了验证这一假设，我们将使用体内和体外模型来确定表面抑制的丧失是否足以引起自发性旁路途径激活，以及I/R后这种表面抑制丧失的机制（SA 1）。因子H是一种有效的旁路途径抑制剂，其以高浓度循环，但在某些疾病中不能预防旁路途径介导的损伤。我们还将研究一种新的补体抑制剂，目标H因子的补体激活的网站，防止肾I/R后的病理性补体激活，和调节内源性H因子（SA 2）保护这个表面的因素。最后，我们将研究替代途径的激活在tubuloacetitium触发广泛的炎症反应（SA 3）的机制。缺血性急性肾衰竭是急性肾衰竭的最常见原因之一，并且在重症监护室环境中与大于50%的死亡率相关。许多补体抑制剂已成为可用的，包括已由我们的实验室开发的旁路途径的特异性抑制剂和由我们的合作者之一开发的旁路途径的靶向抑制剂。拟议的研究应有助于阐明补体抑制作为缺血性急性肾功能衰竭治疗的益处和局限性，以及扩大我们对补体激活作为肾小管损伤后炎症介质的理解。公共卫生相关性缺血性急性肾衰竭是急性肾衰竭的最常见原因之一，并且与重症监护室环境中大于50%的死亡率相关。研究表明，缺血后肾脏内的补体系统被激活。拟议的实验检查补体系统和肾脏之间的复杂相互作用。这些研究将确定有效抑制补体系统的治疗方法，并确定这些药物是否会改善缺血性急性肾衰竭。