Role of DAF in the Complement Cascade

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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.