It is well established that genetics plays a major role in the pathogenesis of systemic lupus erythematosus (SLE). The long-term goal of this project is to understand the genetic control of this disease. During the past several years, we have characterized a new mouse model, NZM2328. Both males and females of this strain have circulating anti-nuclear antibodies (ANA). In the males, acute glomerulonephritis (GN) is seen frequently without severe proteinuria. However, the females have severe proteinuria, acute and chronic GN with early mortality. In a backcross analysis of (NZM2328XC57L/J)F1 X NZM2328, a region of chromosome 1 has been identified to control acute and chronic glomerulonephritis (GN). These have been designated as Agnz1 and Cgnz1. In addition, a locus designated as Adnz1 on chromosome 4 was shown to be linked to the production of anti-ANA and anti-dsDNA antibodies. Two congenic lines, NZM.C57Lc1 and NZM.C57Lc4 were generated by replacing the relevant region in NZM2328 with that of C57L/J respectively. NZM.C57Lc1 females have markedly reduced proteinuria and GN while those of NZM.C57Lc4 have severe proteinuria and GN without ANA. Surprisingly, ANA and anti-dsDNA are not seen in NZM.C57Lc1 suggesting that a locus, Adnz1 on chromosome 1 also contributes to ANA production. These results have led to the hypothesis that separate genes control autoantibody (ANA, anti- histone and anti-dsDNA antibodies) production and end organ damage. This competitive renewal application focuses on the genetic segment on chromosome 1 controlling three distinct phenotypes.
Four specific aims are proposed:
Specific Aim 1 : To generate NZM.C57Lc1 congenic strains and a mapping panel of intrachromosomal recombinants by intercross breeding (F1XF1) to fine map the genetic region of chromosome 1, containing Agnz1, Cgnz1 and Adaz2, which control acute GN, chronic GN and ANA and related Ab production. This will enable us to identify candidate genes in the region relating to each of the three phenotypes;
Specific Aim 2 : To identify a set of contiguous overlapping genomic clones (contigs), which cover the candidate genes of interest and to sequence these contigs to define polymorphisms in the candidate genes;
Specific Aim 3 : To identify the functions of the candidate genes and their role in shaping the observed phenotypes;
and Specific Aim 4 : To validate susceptibility by allele transgenesis or gene knockin technology. The results of this research may identify important checkpoints for the pathogenesis of lupus nephritis, providing new targets for therapeutic intervention.
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