COMPLEMENT REGULATION BY APOLIPOPROTEIN J

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The long term objective is to develop ways to differentially regulate the terminal complement complex (TCC) in order to inhibit its cytolytic activity without interfering with activities that require sublytic insertion of the complex into membranes, e.g., in signal transduction. This would be helpful in such areas as atherosclerosis and Alzheimer's disease, both of which involve complement-mediated cytolysis. Specific aim l is to determine the apolipoprotein J (apoJ) - TCC interactions that are important for the association and inhibition of TCC activity in vitro. To address this question, experiments will be performed to l) ascertain whether apoJ and/or either of its two subunits interferes with the assembly of any individual component into the terminal complex, and 2) determine whether apoJ and/or either of its two subunits can directly inhibit C9 polymerization. Specific aim 2 is to identify apoJ sequences responsible for its interaction with and inhibition of the TCC. Experiments are designed to identify functional domains, specifically those in the alpha subunit, using peptides, and to introduce point mutations into these domains via site-directed mutagenesis to identify functional amino acid residues.