The long-term objective of the proposed research is to evaluate the contribution of the alternative complement pathway in host defense and in the pathogenesis of complement-mediated tissue damage in inflammatory and autoimmune diseases. Currently, there is no experimental animal model to test independently the biologic function of the alternative pathway in vivo. To approach our objective, we will focus our efforts on the following three specific aims: 1). Construct factor D """"""""knockout"""""""" mice. We will utilize gene targeting technology to disrupt the factor D gene in mice and completely eliminate the function of the alternative complement pathway in vivo. 2). Evaluate the contribution of the alternative pathway in host defense. We will utilize type 3 Streptococcus pneumoniae and group B Neisseriae meningiditis to induce experimental bacteremia in factor D-deficient and -sufficient mice. The contribution of the alternative pathway against these encapsulated bacteria will be estimated by measuring blood clearance of bacteria and survival of mice and also by testing opsonization and phagocytosis of bacteria in vitro. 3). Evaluate the contribution of the alternative pathway in inflammatory synovitis. A streptococcal cell wall (SCW)- induced mouse model of acute arthritis representative of human rheumatoid arthritis will be utilized. Arthritis will be induced in both """"""""naive"""""""" and SCW-immunized mice. The participation of the alternative pathway will be studied by analysis of the acute phase of the synovitis in factor D-deficient and -sufficient mice. The information on the pathogenetic activation of the alternative pathway in this mouse model of acute synovitis should be of relevance to the pathogenesis of human inflammatory arthritis. In addition, the complete elimination of the alternative complement pathway in factor D """"""""knockout"""""""" mice should provide valuable guidelines for designing pharmacologic complement inhibitors to control self-tissue damage in related human diseases.

Project Start
1998-01-01
Project End
1998-12-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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