COMPLEMENT RECEPTOR ONE (CR1)--STRUCTURE/FUNCTION

补语系统是宿主先天和后天关系的重要组成部分 获得性免疫防御系统：它服务于识别和 清除微生物、免疫复合体和受损组织。 补体还会在以下情况下造成严重的组织损伤 自身免疫、免疫复合体沉积、再灌注损伤和 异种移植排斥反应。目前，还没有治疗这种疾病的药物。 抑制补体。 补体激活受补体调节因子的控制 激活(RCA)蛋白家族。这其中最多才多艺的成员 家族是红细胞补体受体1(CR1，CD35)：CR1 细胞介导免疫复合物的黏附和递送到 固定吞噬系统而CR1促进白细胞黏附 还有内吞作用。CR1还介导某些C3b涂层的进入 病原体进入淋巴细胞和红细胞，从而导致 传染过程。最近，一种可溶的CR1形式在 补体相关组织抑制因子的几种动物模型 受伤。 CR1与补体激活的几个组成部分相互作用 途径包括C3b、C4b以及C3和C5转化酶。这个 这项应用的长期目标是了解分子 这些相互作用的基础及其在CR1功能中的作用，并设计 补体调节的新治疗工具。建议进行研究 具体目标如下：1)阐明CR1的结构 活性部位和设计对治疗有价值的小CR1类似物 申请。2)了解CR1与 C3b/C4b和转化酶。3)确定生物化学如何 CR1的性质决定了它的细胞表面功能。 这种实验方法将利用基因的定点突变 CR1活性及随后的体外细胞表面和 流体相CR1形成以阐明关键结构/功能关系， 为了定义每个活性区域对生物功能的贡献， 并生产具有治疗潜力的小CR1类似物。

The complement system is an important part of the host's innate and acquired immune defense system: it serves in the identification and elimination of microorganisms, immune complexes and damaged tissue. Complement can also cause profound tissue damage in cases of autoimmunity, immune complex deposition, reperfusion injury, and xenograft rejection. Presently, there is no therapeutic agent for the inhibition of complement. Complement activation is controlled by the Regulators of Complement Activation (RCA) protein family. The most versatile member of this family is Complement Receptor 1 (CR1, CD35): CR1 on red blood cells mediates adherence and delivery of immune complexes to the fixed phagocytic system while CR1 on leukocytes promotes adherence and endocytosis. CR1 also mediates entry of certain C3b-coated pathogens into lymphocytes and RBCs, thus contributing to the infectious process. Recently, a soluble CR1 form has been shown in several animal models to be an inhibitor of complement-related tissue injury. CR1 interacts with several components of the complement activation pathways including C3b, C4b, and the C3 and C5 convertases. The long-term objectives of this application are to understand the molecular basis of these interactions and their role in CR1 function, and to design new therapeutic tools for complement regulation. Studies are proposed with the following specific aims: 1) Elucidate the structure of the CR1 active sites and design small CR1 analogs valuable for therapeutic applications. 2) Understand the mechanism of CR1 interactions with C3b/C4b and the convertases. 3) Determine how the biochemical properties of CR1 direct its cell surface function. The experimental approach would utilize site-directed mutagenesis of the CR1 active and subsequent in vitro assays with cell surface and fluid phase CR1 forms to elucidate key structure/function relationships, to define the contributions of each active region to biolgical function, and to produce small CR1 analogs of therapeutic potential.