EXCEED THE SPACE PROVIDED. The central goal of this proposal is to exploit the use of a new mutant murine strain to advance the understanding of autoimmune disorders. During a gene targeting experiment we serendipitously derived a line of mice that manifest a severe lymphoproliferative and autoimmune disease with Lupus features. The animals develop, as early as 3 month old, a dramatic phenotype characterized by generalized massive lymphadenopathy and splenomegaly that progress in an aggressive manner. In addition, the animals manifest autoimmune pathologies dominated by a severe glomerulonephropathy and hyper- immunoglobulinemia. Most significantly, the animals develop auto antibodies against double-stranded DNA and Sm antigen which are specific markers for systemmic lupus erythrematosus (SLE). Immune function studies revealed that the animals have a profound lymphoid developmental defect that has not been seen in any other model. By back-crossing breeding the disease phenotype segregated from mice with the knockout of the targeted gene and is inheritable as an autosomal recessive trait with a Mendelian frequency consistent with a recessive gene. Therefore the disease is due to the spontaneous mutation of another gene which we have named lag (lymphoproliferation, autoimmune glomerulonephropathy). Using chromosomal satellite markers, the disease locus was mapped to the telomeric end of chromosome 2. This is not a region that has been linked before to autoimmune disease. By candidate gene approach the disease was found to be due to a loss-of-function mutation of the RasGRP1 gene. The central goal of this proposal is study further the role of RasGRP1 in autoimmune disease by Aiml):Studying the mechanisms for disease in Ras GRPlmut animals;
Aim 2) Studying how RasGRP mutation affect T cell development;
Aim3) Studying how RASGRP1MUT allele affect antigen-induced T cell signaling.
and Aim 4) Investigating for evidence of mutation(s) of the RasGRP1 gene in human SLE. This project will contribute to a long term goal of understanding the diverse genetic and molecular basis of autoimmune diseases and add to knowledge for new ways to treat and control autoimmune diseases. PERFORMANCE SITE ========================================Section End===========================================
Showing the most recent 10 out of 20 publications
