The major goal of the studies proposed in this competitive renewal is to define further the genetic contributions to autoimmune disease in New Zealand hybrid mice that is a model of systemic lupus erythematosus (SLE). In previous studies, the investigator showed that the major dominant NZW contribution to disease was linked to H2, the murine major histocompatibility complex. Additional studies have mapped NZB susceptibility loci to chromosomes 1, 4, 7, 13, and 17 at H2. Congenic mice carrying these loci have been generated in the investigator's laboratory with the hypothesis being that each locus underlies an intermediate phenotype that in isolation reflects a single immunopathologic component of overall disease process.
In Specific Aim 1 the investigator proposes to find out whether Ez and Az interact to control disease or if other H2 loci contribute to the MHC affect. Previously, the investigator identified a locus on chromosome 4 in NZB mice (Nba1) that he has introgressed onto NZW. This locus results in increased nephritis and mortality.
In Specific Aim 2, the investigator proposes to identify the intermediate phenotype associated with this locus and to refine the support interval and number of candidate genes via congenic mapping.
In Specific Aim 3, similar studies will be carried out using C57BL/6 and SM/J congenic mice carrying Nba2NZB, an NZB susceptibility locus on chromosome 1. The investigator purports to have identified a lupus-susceptibility locus that maps to chromosome 13 in C57BL/10 mice but is absent in C57BL/6 mice. Therefore, in Specific Aim 4 he proposes to take advantage of what he believes is a unique opportunity to identify this lupus-enhancing gene.
In Specific Aim 5 the investigator proposes to continue to derive and characterize SM/J mice congenic for NZB lupus-susceptibility loci on chromosomes 7 and 13. Taken together, the investigator suggests that the results of the studies proposed in this application will provide new insight into the genes that allow for autoimmune disease in SLE and the intermediate phenotypes that they control.
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