Analysis of the regulation of complement activation

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DESCRIPTION (provided by applicant): Complement is a group of plasma proteins that provide innate immunity through the targeting and degradation of non-self antigens and additionally cooperate with the immune system to destroy targets that are bound by antibodies. To control complement activity, cells express several membrane proteins, including CD46 (membrane cofactor protein; MCP), CD55 (decay accelerating factor; DAF) and CD59 (protectin). Recently, deficiency in a complement regulatory protein, CD46, was linked to a familial type of hemolytic uremic syndrome, a disease caused by complement attack in the blood vessels of the kidney. Surprisingly, three of the four affected families were heterozygous for CD46 deficiency, suggesting that levels of complement regulators are extremely important. Using RNA interference (RNAi), cell lines expressing varying levels of complement regulators will be created and tested to examine the relationship between regulator levels and complement attack. Second, the distribution of complement regulators and effectors at the cell surface will be examined using microscopy. Finally, a RNAi-based screen will be developed to identify pathways that affect the rate of complement deposition at the cell surface.