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: 9251237
• 负责人: Joann B. Sweasy
• 金额: $ 20.71万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251237
• 关键词: African American; American; Amino Acids; Antinuclear Antibodies; Appearance; Autoimmune Diseases; Base Excision Repairs; Biological Markers; CRISPR/Cas technology; Cell Death; Cells; 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; 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 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，目前尚无治愈这种疾病的方法，该疾病影响大量美国人，主要是非裔美国人女性。先前的研究表明，在小鼠模型中，异常的碱基切除修复会导致狼疮的发生，而在一小部分狼疮患者中，DNA 断裂的修复受到损害。结合起来，这些研究指出了异常 DNA 修复在 SLE 发展中的作用，但对于遗传基础，特别是 DNA 修复基因的种系突变是否与 SLE 患者的相关性，人们知之甚少。我们在狼疮联盟中发现了与 SLE 相关的 PARP1 基因中的遗传变异 (GV)，该变异编码多聚 ADP 核糖聚合酶，其具有多种细胞作用，其中最明确的 GV 是在 DNA 修复中发挥作用。该研究的长期目标是确定异常的 DNA 修复是否会导致 SLE。该探索性项目的重点是检验 PARP1 GV 有可能导致狼疮发生的假设。该应用的具体目标是 1) 检验小鼠的假设。携带 PARP1 GV 的小鼠会患上狼疮；2) 为了检验我们已确定的与人类 SLE 相关的 PARP1 SNP 会导致 DNA 修复受损的假设，为了实现这些目标，我们将生成携带 PARP1 GV 的小鼠并描述狼疮的发展特征。我们还将表征组织培养细胞中的这种变异参与 DNA 修复的能力，并表征具有 PARP1 变异的个体的淋巴细胞，以确定它们是否损害了 DNA 修复。对我们的假设进行了严格的检验，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。