The Role of a PARP1 Genetic Variant in Development of Lupus

 描述（由申请人提供）：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影响大量美国人和主要是非洲裔美国人血统的女性的疾病。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中狼疮的发展。以前的研究表明，DNA断裂的修复在狼疮患者的小子集中受到损害。综合起来，这些研究指出了异常DNA修复在SLE发展中的作用。然而，对遗传基础知之甚少，特别是DNA修复基因的生殖系突变是否与SLE患者有关。在与狼疮协会成员的合作中，我们已经确定了PARP1基因中与SLE相关的遗传变异（GV）。PARP1编码聚ADP核糖聚合酶，其具有许多细胞作用，其中最好的特征在于DNA修复。我们已经发现GV位于PARP1的外显子内，并预测其会导致受损PARP1蛋白的表达，这可能导致异常DNA修复和SLE的发展。这项研究的长期目标是确定异常DNA修复是否会导致SLE的发展。这个探索性项目的重点是测试PARP1 GV有可能导致狼疮发展的假设。本申请的具体目的是1）测试携带PARP1 GV的小鼠发展狼疮的假设，和2）测试我们已经鉴定为与人类SLE相关的PARP1 SNP导致受损的DNA修复的假设。为了实现这些目标，我们将产生携带PARP1 GV的小鼠并表征狼疮的发展。我们还将在组织培养细胞中表征这种变体参与DNA修复的能力，并表征具有PARP1变体的个体的淋巴细胞，以确定它们是否具有受损的DNA修复。这个探索性的项目将为我们的假设提供一个严格的测试，并有可能提供关于异常DNA修复和狼疮之间联系的机制见解。

 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.