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

描述（由申请人提供）：补体系统是先天免疫的主要参与者，也是体液免疫应答的效应臂。通过天然抗体、凝集素和旁路途径（AP），特别是AP的反馈环，补体系统激活微生物并改变自身。目标是损伤、凋亡和坏死的细胞、碎片的积累和微生物病原体。随着年龄的增长，脂质存款在血管壁（动脉粥样硬化），尿酸盐在关节（痛风），淀粉样蛋白在大脑（阿尔茨海默病- AD）和脂褐素色素（玻璃疣）在视网膜（年龄相关性黄斑变性- 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，特别是扩增环，对于免疫稳态和防止重要器官中的不期望的活化是至关重要的。这项资助提案的目标是建立在与补体的关键C3 b片段与受体和调节剂的相互作用有关的先前贡献的基础上，并通过以下方式进一步探索其作为组装反馈回路的病灶的作用：1）评估C3 b与其调节剂和受体的相互作用，目的是表征易患非典型溶血性尿毒综合征（阿胡斯）的C3中的新杂合突变，以及与年龄相关的C3中的多态性，相关性黄斑变性和肾移植存活率; 2）进一步确定补体受体1型的结构和功能（CR 1; CD 35），包括分析最近鉴定的与人类疾病相关的突变; 3）采用新产生的动物模型Crry-单基因敲除（SKO）小鼠，和Crry小鼠来检查体内补体调节，重点是AP反馈环的稳态，并评估其中AP介导病理后果的人类疾病模型。拟议实验的一个基本假设是，AP不断在细胞上翻转，从而充当外来因子和改变的自我的监视系统。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作出反应。它涉及许多常见的人类疾病，其特征是大脑中蛋白质的沉积改变（阿尔茨海默病），血管壁中的脂质（心脏病发作和中风）和视网膜中的色素（年龄相关性黄斑变性）。在这些重要器官中的慢性炎症是不希望的。此外，包括疟疾寄生虫在内的许多病原体，对世界上许多地区来说都是一个主要的健康风险，它们利用先天免疫参与者来入侵，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一些最常见和致命疾病的理解。

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.