COMPLEMENT RECEPTOR ONE (CR1)--STRUCTURE/FUNCTION

补体系统是宿主先天免疫系统的重要组成部分， 获得性免疫防御系统：它在识别和 消除微生物、免疫复合物和受损组织。 补体也可导致严重的组织损伤， 自身免疫、免疫复合物沉积、再灌注损伤，以及 异种移植排斥反应 目前，还没有治疗药物用于 补体抑制。 补体激活由补体调节因子控制 活化（RCA）蛋白家族。 最多才多艺的成员 补体受体1（CR 1，CD 35）：红细胞上的CR 1 细胞介导免疫复合物粘附和递送至细胞， 固定吞噬系统，而白细胞上的CR 1促进粘附 和内吞作用。 CR 1还介导某些C3 b包被的 病原体进入淋巴细胞和红细胞，从而有助于 传染过程 最近，可溶性CR 1形式已在 几种动物模型是补体相关组织的抑制剂 损伤 CR 1与补体激活的几个组分相互作用 包括C3 b、C4 b以及C3和C5转化酶的途径。 的 本申请的长期目标是了解分子 这些相互作用的基础及其在CR 1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CR 1的结构 活性位点和设计小的CR 1类似物， 应用. 2)了解CR 1与 C3 b/C4 b和转化酶。 3)确定生物化学是如何 CR 1的特性指导其细胞表面功能。 该实验方法将利用定点诱变， CR 1活性和随后的细胞表面体外试验， 形成流体相CR 1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， 并产生具有治疗潜力的小CR 1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.