Cellular and Genetic Basis of Systemic Lupus

描述（由申请人提供）：众所周知，遗传学在系统性红斑狼疮（SLE）的发病机制中起主要作用。该项目的长期目标是了解这种疾病的遗传控制。在过去的几年中，我们已经表征了一种新的小鼠模型NZM 2328。该菌株的雄性和雌性都有循环抗核抗体（ANA）。在男性，急性肾小球肾炎（GN）是常见的，没有严重的蛋白尿。然而，女性有严重的蛋白尿，急性和慢性肾小球肾炎，早期死亡。在（NZM 2328 XC 57 L/J）F1 X NZM 2328的回交分析中，已经鉴定了控制急性和慢性肾小球肾炎（GN）的1号染色体区域。它们被命名为Agnz 1和Cgnz 1。此外，在4号染色体上被指定为Adnz 1的基因座显示与抗ANA和抗dsDNA抗体的产生相关。将NZM 2328的相应区域分别替换为C57 L/J的相应区域，获得了两个同源系NZM. C57 Lc 1和NZM. C57 Lc 4。NZM.C57Lc1雌性动物的蛋白尿和GN显著减少，而NZM.C57Lc4雌性动物的蛋白尿和GN严重，但无ANA。令人惊讶的是，在NZM.C57Lc1中未观察到ANA和抗dsDNA，这表明1号染色体上的基因座Adnz 1也有助于ANA的产生。这些结果导致了单独的基因控制自身抗体（ANA、抗组蛋白和抗dsDNA抗体）产生和终末器官损伤的假设。这种竞争性更新应用集中在控制三种不同表型的1号染色体上的遗传片段。提出了四个具体目标：具体目标1：通过杂交育种（F1 XF 1）产生NZM.C57Lc1同源菌株和染色体内重组体的定位组，以精细定位1号染色体的遗传区域，包含Agnz 1，Cgnz 1和Adaz 2，其控制急性GN，慢性GN和ANA以及相关Ab产生。这将使我们能够识别与三种表型中的每一种相关的区域中的候选基因;具体目标2：识别一组连续重叠的基因组克隆（重叠群），其覆盖感兴趣的候选基因，并对这些重叠群进行测序以定义候选基因中的多态性;具体目标3：识别候选基因的功能及其在形成观察到的表型中的作用;具体目标4：通过等位基因转基因或基因敲入技术验证易感性。这项研究的结果可能会确定狼疮肾炎发病机制的重要检查点，为治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): 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.