CD46: Protecting the Host from Complement Attack

膜辅因子蛋白(MCP，CD46)是一种结合C3b和C4b的补体调节蛋白 并作为它们有限的蛋白质降解的辅助因子。过去的一项重大发展 Grant Cycle是发现CD46突变易患非典型血型尿毒症综合征 (AHUS)。这一发现对治疗方案产生了直接影响，因为肾移植将是 治疗CD46缺乏症。这一点尤其重要，因为HUS可能是一种危及生命的疾病 这种情况在大约50%发生肾功能衰竭的患者(通常是年幼的儿童)中会复发。非典型HUS 现在被认为是一种由于补体调节突变而导致的补体失调症 蛋白质。我们将解决CD46缺陷是如何导致AHUS的。 这笔赠款的一个主要目标是表征CD46的S调节活动的原位特征。AHUS和AHUS患者 他们的家庭，我们将1)建立一个设施来识别突变并确定其功能谱系 2)使用模型系统(表达突变蛋白的CHO细胞，EB病毒 来自aHUS家族的转化的人B淋巴细胞和人内皮细胞)，评估抑制 原位活性；RNAi将被用来创造具有特定抑制物缺乏状态的细胞；3)使用 单链抗体补体调节因子(S)嵌合体靶向抑制红细胞和内皮细胞以纠正 并确定抑制补体激活最有效的调节剂组合；4) 监测调节器的膜运动，因为它们与抗体和病原体以及在 对补体激活的反应。这些具体施舍背后的一个主题是探索这个过程 由此宿主限制了对改变和受损的自身细胞的补体激活。我们已经发现了这种现象 被称为TRACS的补体系统的靶向和限制性激活，研究甚少。我们 提出补体在自体组织上的激活谱具有独特的目的和鲜明的特征 与其在微生物上的激活相比。我们的长期目标是了解如何使用 CD46缺乏症在aHUS中的应用 我们的建议将有助于确定补体调节因子CD46的缺陷如何易患人类 疾病溶血性尿毒症综合征以及开发提供治疗这种疾病的调节剂的方法。

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.