Role of DAF in the Complement Cascade

描述（由申请人提供）：衰减加速因子（DAF）是一种70 kDa的内在膜调节剂，可保护自身细胞免受自体补体介导的损伤。它通过衰变C3中枢转换酶（C4b2a和C3bBb）起作用，这一过程决定了补体激活是终止还是继续。通过之前的诱变研究和核磁共振结构分析，我们暂时绘制了DAF的活性位点。在其他工作中，我们制备了Daf敲除小鼠，并开始表征Daf在不同自身免疫/炎症状态下的生理重要性。

DESCRIPTION (provided by applicant): Decay accelerating factor (DAF) is a 70 kDa intrinsic membrane regulator that protects self cells from autologous complement-mediated injury. It functions by decaying the C3 central convertases (C4b2a and C3bBb), a process which determines whether complement activation aborts or proceeds. Through previous mutagenesis studies and NMR structural analyses, we have provisionally mapped DAF's active site(s). In other work, we have prepared Daf knockout mice and have begun to characterize DAF's physiological importance in different autoimmune/inflammatory states. Our proposed research is designed to provide insights into several unresolved questions concerning DAF's function. Aim 1 focuses on precisely characterizing DAF's interface with the C3 convertases and defining its molecular mechanism of action. This should provide a basis not only for understanding DAF's function but for unraveling the actions of other C3 convertase regulators. Aim 2 focuses on further clarifying DAF's overall physiological function in vivo. This should shed important insights into the pathogeneses of a number of disorders as well as new information on immune regulation and immune effector function. Aim 3 focuses on a) characterizing the transcriptional mechanisms controlling expression levels of DAF and other intrinsic regulators and b) targeting exogenous recombinant DAF derivatives to specific sites in vivo. This latter work is relevant not only to autoimmune/inflammatory disorders but potentially also to neoplasia. New findings concerning pharmacological manipulation of the proteins' expression levels via transcriptional mechanisms could open the way to new approaches to therapy.