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，也是体液免疫反应的效应臂。通过天然抗体、凝集素和替代途径（AP），特别是AP的反馈回路，补体系统激活微生物和改变自我。损伤的、凋亡的和坏死的细胞、碎片的积累和微生物病原体都是目标。随着年龄的增长，脂质沉积在血管壁（动脉粥样硬化），尿酸沉积在关节（痛风），淀粉样蛋白沉积在大脑（阿尔茨海默病- AD），脂褐素色素沉积在视网膜（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，特别是放大回路，对免疫稳态和防止重要器官的不良激活至关重要。本拨款提案的目标是建立在补体关键C3b片段与受体和调节因子相互作用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中心的作用：1)评估C3b与其调节因子和受体的相互作用，目的是表征C3中易患非典型溶血性尿毒症综合征（aHUS）的新型杂合突变，以及C3中与年龄相关性黄斑变性和肾移植生存相关的多态性；2)进一步确定补体受体1型（CR1; CD35）的结构和功能，包括分析最近发现的与人类疾病相关的突变；3)采用新生成的动物模型，Crry-单敲除（SKO）小鼠和Crry小鼠来研究体内补体调控，重点关注AP反馈回路的稳态，并评估AP介导病理后果的人类疾病模型。所提出的实验的一个基本假设是，AP不断地在细胞上翻转，从而充当监视外来代理人和改变自我的系统。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。它与许多常见的人类疾病有关，包括大脑中改变的蛋白质沉积（阿尔茨海默病），血管壁中的脂质沉积（心脏病发作和中风）和视网膜中的色素沉积（年龄相关性黄斑变性）。这些重要器官的慢性炎症是不可取的。此外，许多病原体，包括疟疾寄生虫，对世界上许多人的主要健康风险，利用先天免疫玩家入侵，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一些最常见和致命的人类疾病的理解。

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.