The Role of a PARP1 Genetic Variant in Development of Lupus

PARP1 基因变异在狼疮发展中的作用

• 批准号: 9092164
• 负责人: Joann B. Sweasy
• 金额: $ 26.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9092164
• 关键词: African American; American; Amino Acids; Antinuclear Antibodies; Appearance; Autoimmune Diseases; Base Excision Repairs; Biological Markers; Cell Death; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collaborations; DNA; DNA Polymerase beta; DNA Repair; DNA Repair Gene; DNA Sequence Alteration; DNA glycosylase; DNA replication fork; DNA-(apurinic or apyrimidinic site) lyase; Data; Deposition; Development; Disease; Enzymes; Etiology; Excision; Exons; Female; Genes; Genetic; Genomic Instability; Germ-Line Mutation; Goals; Grant; Human; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Individual; Kidney; Kidney Diseases; Knowledge; Laboratories; Lead; Learning; Left; Link; Lupus; Lymphocyte; Malignant Neoplasms; Metabolism; Missense Mutation; Monitor; Mus; Mutate; Mutation; Nucleotides; Oxygen; Patients; Phenotype; Poly(ADP-ribose) Polymerases; Polymerase; Process; Proteins; Reactive Oxygen Species; Research; Ribose; Role; Single Nucleotide Polymorphism; Site; Specificity; Systemic Lupus Erythematosus; Technology; Testing; V(D)J Recombination; Variant; Work; base; effective therapy; exome; genetic analysis; genetic variant; insight; member; mouse model; public health relevance; repaired; rheumatologist; tissue/cell culture

 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.

 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。目前尚无治愈这种影响大量美国人且主要是非裔美国人血统女性的疾病的方法。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会导致小鼠模型中狼疮的发生。先前的研究表明，一小部分狼疮患者的 DNA 断裂修复受到损害。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，人们对遗传基础知之甚少，特别是 DNA 修复基因的种系突变是否与患者的 SLE 相关。我们与狼疮联盟成员合作，在 PARP1 基因中发现了与 SLE 相关的遗传变异 (GV)。 PARP1 编码 PolyADP 核糖聚合酶，它具有多种细胞作用，其中最明确的作用是在 DNA 修复中。我们发现的 GV 位于 PARP1 的一个外显子内，预计会导致受损的 PARP1 蛋白表达，从而可能导致异常 DNA 修复和 SLE 的发展。该研究的长期目标是确定异常 DNA 修复是否会导致 SLE 的发生。这个探索性项目的重点是检验 PARP1 GV 有可能导致狼疮发展的假设。该申请的具体目标是 1) 检验携带 PARP1 GV 的小鼠会患狼疮的假设，以及 2) 检验我们已确定与人类 SLE 相关的 PARP1 SNP 导致 DNA 修复受损的假设。为了实现这些目标，我们将培育携带 PARP1 GV 的小鼠并表征狼疮的发展。我们还将表征组织培养细胞中的这种变体参与 DNA 修复的能力，并表征具有 PARP1 变体的个体的淋巴细胞，以确定它们是否损害了 DNA 修复。这个探索性项目将对我们的假设进行严格的检验，并有可能提供有关异常 DNA 修复与狼疮之间联系的机制见解。