CD46: Protecting the Host from Complement Attack

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DESCRIPTION (provided by applicant): Membrane cofactor protein (MCP, CD46) is a complement regulatory protein that binds C3b and C4b and serves as a cofactor for their limited proteolytic degradation. A major development during the past grant cycle was the discovery that mutations in CD46 predispose to atypical hemolytlc 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 young children) with about 50% developing renal failure. Atypical HUS is now recognized as a disease of complement deregulation due to mutations in complement regulatory proteins. We will address how CD46 deficiency predisposes to 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 (CHO cells expressing the mutant proteins, EB virus transformed human B lymphocytes from aHUS families, and human endothelial cells), assess Inhibitory activity in situ; RNAi will 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 explore the process whereby the host limits complement activation on altered and injured self cells. This phenomenon we have 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 syndrome as well as develop ways to deliver regulators to treat such conditions