Principal Investigator/Program Director (Last, first, middle): Boackle, Susan A. DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This abstract is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, as is, will become public information. Therefore, do not inctude prophetary/confidentiat information. DO NOT EXCEED THE ,SPACE PROVIDED. The major murine systemic lupus erythematosus (SLE) susceptibility locus, Slel, corresponds to 3 loci independently affecting loss of tolerance to chromatin in the NZM2410 mouse. The congenic interval corresponding to Slelc, derived from NZW, contains Cr2, which encodes complement receptors I and 2 (CR1/CR2, CD35/CD21). CR1/CR2 deficiency has been associated with autoimmune disease in both humans and in animal models. A structural difference in a critical ligand-binding domain has recently been identified in Slelc CR1/CR2 which results in significant impairment in receptor function. These results strongly support the role of Cr2 as a disease susceptibility gene in the Slelc interval. The project outlined in this proposal will be directed towards characterizing the role of NZW CR2 in the NZM2410 mouse model for lupus.
The specific aims are to prove that CR2 is the lupus susceptibility gene in the NZM2410 Slelc interval, to identify the structural domains in NZW CR2 that are critical in loss of tolerance, and to determine the mechanisms by which NZW CR2 results in loss of tolerance. Proof that CR2 is the lupus susceptibility gene in the Slelc locus will be provided by demonstrating that the Slelc phenotypes resolve in the presence of normal gene products. Recombinant strains that contain narrowed intervals containing Cr2 will be assessed to ensure that CR2 dysfunction continues to track with autoimmune disease, The critical receptor domains that result in the autoimmune phenotypes will be determined, using both CR2-deficient cell lines transfected with recombinant proteins as well as B cells from BAC transgenic mice that express various forms of the polymorphic NZW CR2. Finally, the mechanisms by which the altered NZW CR2 allele results in loss of B cell tolerance will be characterized using the 3-83 and HEL models for B cell tolerance. These studies will clarify the specific functions of CR2, impaired in the NZM2410 mouse model, that may impact on the development of autoimmune disease and thus be important targets for therapeutic interventions. PERFORMANCE SITE ========================================Section End===========================================
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