The Role of a PARP1 Genetic Variant in Development of Lupus

 描述(申请人提供)：系统性红斑狼疮(SLE)是一种病因不明的自身免疫性疾病。目前还没有治愈这种疾病的方法，这种疾病影响了相当数量的美国人，主要是非洲裔美国人后裔的女性。我们实验室最近的研究提供了证据表明，异常的碱基切除修复导致小鼠模型狼疮的发生。先前的工作表明，在狼疮患者的小亚群中，DNA断裂的修复受到了损害。综上所述，这些研究指出了DNA异常修复在系统性红斑狼疮发生发展中的作用。然而，人们对其遗传基础知之甚少，特别是DNA修复基因的胚系突变是否与患者的系统性红斑狼疮有关。在与狼疮联盟成员的合作中，我们已经确定了PARP1基因中的一个与SLE相关的遗传变异(GV)。PARP1编码PolyADP核糖聚合酶，具有多种细胞功能，其中最重要的是DNA修复。我们发现的GV位于PARP1的一个外显子内，预计会导致PARP1蛋白的表达受损，从而可能导致DNA修复异常和SLE的发展。这项拟议研究的长期目标是确定异常的DNA修复是否会导致SLE的发展。这一探索性项目的重点是检验PARP1GV有可能导致狼疮发生的假设。该应用程序的具体目标是1)测试携带PARP1 GV的小鼠患狼疮的假设，以及2)测试我们已确定与人类SLE相关的PARP1 SNP导致DNA修复受损的假设。为了实现这些目标，我们将产生携带PARP1GV的小鼠，并对狼疮的发展进行表征。我们还将在组织培养细胞中鉴定该变体参与DNA rPair的能力，并鉴定带有PARP1变体的个体的淋巴细胞，以确定他们是否有受损的DNA修复。这个探索性的项目将对我们的假设进行严格的测试，并有可能提供关于异常DNA修复和狼疮之间的联系的机械性见解。

 DESCRIPTION (provided by applicant): Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown etiology. There is currently no cure for this disease that effects substantial numbers of Americans and predominantly females of African-American ancestry. Recent research from our laboratory has provided evidence that aberrant base excision repair leads to the development of lupus in a mouse model. Previous work has shown that the repair of breaks in DNA is compromised in small subsets of lupus patients. In combination, these studies point to a role for aberrant DNA repair in the development of SLE. However, little is known about the genetic basis, and specifically whether germline mutations in DNA repair genes are linked to SLE in patients. In collaboration with members of the Lupus Consortium we have identified a genetic variant (GV) in the PARP1 gene that is associated with SLE. PARP1 encodes PolyADP Ribose Polymerase, which has many cellular roles with the most well characterized being in DNA repair. The GV we have discovered is within an exon of PARP1 and is predicted to lead to expression of a compromised PARP1 protein that may lead to aberrant DNA repair and the development of SLE. The long-term goal of the proposed research is to determine if aberrant DNA repair leads to the development of SLE. The focus of this exploratory project is to test the hypothesis that the PARP1 GV has potential to lead to the development of lupus. The Specific Aims of the application are 1) To test the hypothesis that mice harboring the PARP1 GV develop lupus and 2) To test the hypothesis that the PARP1 SNP we have identified as being linked to SLE in humans results in compromised DNA repair. To achieve these aims we will generate mice harboring the PARP1 GV and characterize the development of lupus. We will also characterize this variant in tissue culture cells for its ability to participate in DNA rpair and characterize the lymphocytes of individuals with the PARP1 variant to determine if they have compromised DNA repair. This exploratory project will provide a rigorous test of our hypothesis and has the potential to provide mechanistic insights regarding the link between aberrant DNA repair and lupus.