CD46: Protecting the Host from Complement Attack

膜辅因子蛋白（MCP，CD 46）是一种补体调节蛋白，与补体C3 b和C4 b结合 并作为其有限蛋白降解的辅因子。过去的一个重大发展过去的一个重大发展 格兰特循环是发现CD 46突变易患非典型性溶血性尿毒综合征 （阿胡斯）.这一发现对治疗选择有直接影响，因为肾移植将是一种治疗选择。 治疗CD 46缺乏症。这一点尤其重要，因为阿胡斯可能是一种危及生命的疾病 在约50%发展为肾衰竭的患者（通常为婴幼儿）中复发。非典型HUSis 现在被认为是由于补体调节基因突变引起的补体失调性疾病， proteins.我们将讨论CD 46缺陷是如何产生阿胡斯的。 这项资助的一个主要目标是表征CD 46的原位调节活性。在阿胡斯患者中， 他们的家庭，我们将1）建立一个设施，以确定突变和确定功能的剧目， 突变蛋白; 2）使用模型系统（表达突变蛋白的CHO细胞，EB病毒 来自阿胡斯家族的转化的人B淋巴细胞和人内皮细胞），评估抑制性 原位活性; RNAi将用于产生具有特异性抑制剂缺乏状态的细胞; 3）采用 scFv-补体调节因子嵌合体将抑制剂靶向RBC和内皮细胞，以校正 缺陷，并确定最有效的抑制性混合调节剂，以阻止补体激活; 4） 监测调节剂与抗体和病原体交联时的膜运动， 对补体激活的反应。这些具体的施舍背后的一个主题是探索这个过程 由此宿主限制补体对改变的和损伤的自身细胞的激活。这种现象， 称为TRACS，用于补体系统的靶向和限制性激活，很少被研究。我们 提出补体激活自身组织的模式具有独特的目的和独特的特征 相比之下，它对微生物的激活。我们的长期目标是了解如何使用 阿胡斯中的CD 46缺陷作为说明性实例。 我们的建议将有助于确定补体调节因子CD 46的缺乏如何使人类 疾病溶血性尿毒症综合征以及开发提供调节剂来治疗此类病症的方法。

Membrane cofactor protein (MCP, CD46) is a complement regulatory protein that binds C3b andC4b and serves as a cofactor for their limited protedytic degradation. A major developmentduring the past grant cycle was the discovery that mutations in CD46 predispose to atypical hemotytlc uremic syndrome (aHUS). This finding has an Immediate impact on treatment options since renal transplantation would be curative in CD46 deficiency. This is especially significant since aHUS can be a life-threatening condition that recurs in patients (usually youngchildren) with about 50%developing renal failure. Atypical HUSis now recognized as a disease of complement deregulation due to mutations in complement regulatory proteins. We will address how CD46 deficiency prodtepoeesto aHUS. A major goal of this grant is to characterize CD46's regulatory activity in situ. In patients with aHUS and their families, we will 1) establish a facility to identify mutations and determine the functional repertoire of the mutant proteins; 2) use model systems(CHOcells expressing the mutant proteins, EB virus transformed human B lymphocytes from aHUS families, and human endothelial cells), assess Inhibitory activity in situ; RNAiwill be employed to create cells with a specific inhibitor deficiency state; 3) employ scFv-complement regulator(s) chimeras to target inhibitors to RBCs and endothelial cells in order to correct the deficiency and to define the most potent inhibitory mix of regulators to block complement activation; 4) monitor membrane movements of regulators as they are cross-linked with Abs and pathogens and in response to complement activation. A theme underlying these specific alms is to explorethe process whereby the host limits complement activation on altered and injured self cells. This phenomenon wehave termed TRACS, for targeted and restricted activation of the complement system, is little studied. We propose that the profile of complement activation on self-tissue has unique purposes and distinct features compared to its activation on microbes. Our long term goal is to understand how this is accomplished using CD46 deficiency In aHUS as the Illustrative example. Our proposal will help define how deficiency of the complement regulator CD46 predisposes to human disease hemolytic uremic syndromeas well as develop ways to deliver regulators to treat such conditions.