We are seeking funding to study mouse homologues of the human Regulators of Complement Activation (RCA) gene family. These homologues include mouse Complement Receptors 1 (MCR1) and 2 (MCR2) in addition to Crry/p65, a novel mouse intrinsic complement regulatory protein. Membrane RCA proteins are proposed to play fundamental roles in the physiology of the normal immune response in addition to autoimmune diseases, reproductive biology, hyperacute transplantation rejection, and tumor cell resistance to cytolysis. In order to ultimately study the in vivo roles of these proteins and experimentally manipulate their activities, we propose to establish a mouse model system. However, the structure and biologic roles of mouse homologues of this family, including human CR1, CR2, and the intrinsic complement regulatory proteins Decay-accelerating Factor (DAF) and Membrane Cofactor Protein (MCP), have not been well understood. We have identified and characterized three mouse homologues (MCR1, MCR2, and Crry/p65) using both genetic and immunochemical criteria. We now propose to study in detail structural and functional characteristics of these proteins and compare them to the human family. In addition, we will create new monoclonal and polyclonal antibodies with the ability to detect the proteins in vivo and to block specific activities in vitro and ultimately in vivo. We also propose to create soluble forms of these proteins which block receptor activities and/or exhibit complement regulatory activity. Finally, we will determine the structure, biosynthetic characteristics and cell specific expression of Crry/p65, which we have determined to be a novel complement regulatory protein functionally analogous in vitro to human MCP and likely DAF.
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