C3, CR1, CRRY: INTERACTIONS, HOMEOSTASIS AND TRANSLATIONAL IMPLICATIONS

C3、CR1、CRRY：相互作用、稳态和翻译意义

基本信息

批准号：
8215707
负责人：
John Atkinson
金额：
$ 37.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215707
关键词：
Abdominal Aortic Aneurysm Active Sites Address Adherence Age Age related macular degeneration Alzheimer&apos s Disease Amyloid Proteins Animal Model Antigen-Antibody Complex Apoptotic Applications Grants Area Atherosclerosis Autoantibodies Binding Binding Sites Biological Assay Biology Blood Vessels Brain CD46 Antigen CD55 Antigens Cells Chronic Clinical Cloning Complement Complement 3 Convertase Complement 3b Complement 3b Receptors Complement 3c Complement 4b Complement Activation Complement Factor B Complement Factor D Complement Receptor Complex Deposition Disease Disease Association Disease model Drusen Engineering Feedback Garbage Genetic Polymorphism Genetic Variation Glomerulonephritis Goals Gout Grant Health Hemolysis Hemolytic-Uremic Syndrome Homeostasis Human Immune Immune response Immune system Inflammation Invaded Investigation Joints Kidney Transplantation Knockout Mice Laboratories Lead Lectin Ligand Binding Lipids Lipofuscin Lupus Mediating Membrane Membranoproliferative Glomerulonephritis Microbe Modeling Monitor Mus Mutagenesis Mutation Myocardial Infarction Natural Immunity Necrosis Organ Parasites Pathologic Pathway interactions Pigments Properdin Proteins Publications Regulation Relative (related person)Reproduction Retina Risk Role Site Stroke Structure Structure-Activity Relationship Surface Plasmon Resonance System Systemic Lupus Erythematosus T-Lymphocyte Technology Tissues Transplantation Urate arm base cofactor complement C3 precursor complement system decay acceleration genetic regulatory protein glycosylation human disease in vivo injured insight man microbial microorganism mouse model novel pathogen prevent protein structure function public health relevance receptor receptor structure function research study wasting

项目摘要

DESCRIPTION (provided by applicant): The complement system is a major player in innate immunity and an effector arm of the humoral immune response. Through natural Abs, lectins and the alternative pathway (AP), especially the AP's feedback loop, the complement system activates on microbes and altered self. Injured, apoptotic and necrotic cells, accumulations of debris, and microbial pathogens are targets. As we age, lipids deposit in blood vessel walls (atherosclerosis), urate in joints (gout), amyloid proteins in the brain (Alzheimer's disease - AD) and lipofuscin pigments (drusen) in the retina (age-related macular degeneration - AMD). These body "wastes" or "garbage" become substrates for complement activation, leading to chronic inflammation. Thus, regulation of the complement system, particularly the amplification loop, is critical to immune homeostasis and to prevent undesirable activation in vital organs. The goal of this grant proposal is to build on prior contributions relating to interactions of the complement's key C3b fragment with receptors and regulators and to further explore its role as a nidus for assembling the feedback loop by: 1) assessing C3b interactions with its regulators and receptors, with a goal of characterizing novel heterozygous mutations in C3 that predispose to atypical hemolytic uremic syndrome (aHUS) and on a polymorphism in C3 associated with age-related macular degeneration and renal transplant survival; 2) further defining the structure and function of complement receptor type one (CR1; CD35), including analyzing recently identified mutations associated with human disease; and 3) employing a newly generated animal model, the Crry-single knockout (SKO) mouse, and the Crry mouse to examine complement regulation in vivo with a focus on homeostasis of the AP's feedback loop and to assess models of human disease in which the AP mediates pathologic consequences. An underlying hypothesis for proposed experiments is that the AP is continuously turning over on cells and thereby serves as a surveillance system for foreign agents and altered self. PUBLIC HEALTH RELEVANCE: The innate immune system responds to microorganisms and damaged host tissue. It is involved in many common human diseases featuring deposition of altered proteins in the brain (Alzheimer Disease), lipids in vessel walls (heart attacks and strokes) and pigments in the retina (age-related macular degeneration). Chronic inflammation in such vital organs is undesirable. Also, many pathogens including the malarial parasite, a major health risk for much of the world, take advantage of innate immune players to invade, infect, and injure. These studies will enhance our understanding of how the innate immune system participates in some of the most common and lethal diseases of man.

描述（由申请人提供）：补体系统是先天免疫的主要参与者，也是体液免疫反应的效应子部门。通过天然ABS，凝集素和替代途径（AP），尤其是AP的反馈回路，补体系统在微生物上激活并改变了自我。受伤，凋亡和坏死细胞，碎屑的积累以及微生物病原体是靶标。随着年龄的增长，脂质沉积在血管壁（动脉粥样硬化），关节中的尿酸盐（痛风），大脑中的淀粉样蛋白（阿尔茨海默氏病-AD）和叶片中的脂肪霉素色素（Drusen）（与年龄相关的黄斑变性 - AMD -AMD）。这些身体“废物”或“垃圾”成为补体激活的底物，导致慢性炎症。因此，补体系统的调节，尤其是放大环对免疫稳态至关重要，并防止重要器官中的不良激活。 The goal of this grant proposal is to build on prior contributions relating to interactions of the complement's key C3b fragment with receptors and regulators and to further explore its role as a nidus for assembling the feedback loop by: 1) assessing C3b interactions with its regulators and receptors, with a goal of characterizing novel heterozygous mutations in C3 that predispose to atypical hemolytic uremic syndrome (aHUS) and on与年龄相关的黄斑变性和肾移植存活相关的C3中的多态性； 2）进一步定义补体一型受体的结构和功能（CR1； CD35），包括分析最近确定与人类疾病相关的突变； 3）采用新生成的动物模型，Crry-Single敲除（SKO）小鼠和Crry小鼠在体内检查补体调节，重点是AP反馈循环的体内稳态，并评估AP介导病理后果的人类疾病模型。提出的实验的一个基本假设是，AP正在连续关闭细胞，从而作为外国药物和自我改变的监视系统。公共卫生相关性：先天免疫系统对微生物和受损的宿主组织反应。它参与了许多常见的人类疾病，这些疾病具有大脑中蛋白质改变的沉积（阿尔茨海默氏病），血管壁中的脂质（心脏病发作和中风）以及视网膜中的颜料（与年龄相关的黄斑变性）。这种重要器官中的慢性炎症是不可取的。此外，许多病原体包括疟疾寄生虫，这是全世界大部分地区的主要健康风险，都利用了先天的免疫参与者入侵，感染和伤害。这些研究将增强我们对先天免疫系统如何参与人类最常见和致命疾病的理解。