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（由适用提供）：全身性红斑狼疮（SLE）是一种不明病因的自身免疫性疾病。目前，这种疾病尚无治愈能够影响大量美国人和主要是非裔美国人血统的女性。我们实验室的最新研究提供了证据，表明异常的基本意外修复会导致小鼠模型中狼疮的发展。先前的工作表明，在小狼疮患者的小亚群中，DNA中断裂的修复受到损害。结合起来，这些研究表明了异常DNA修复在SLE开发中的作用。但是，对遗传基础，特别是DNA修复基因中的种系突变是否与患者的SLE有关。与狼疮联盟成员合作，我们确定了与SLE相关的PARP1基因中的遗传变异（GV）。 PARP1编码PolyAdp核糖聚合酶，该聚合酶具有许多细胞作用，最有特征在DNA修复中。我们发现的GV在PARP1的外显子内，预计会导致折衷的PARP1蛋白表达，这可能导致异常的DNA修复和SLE的发展。拟议的研究的长期目标是确定异常的DNA修复是否导致SLE的发展。该探索性项目的重点是检验以下假设：PARP1 GV有可能导致狼疮的发展。应用程序的具体目的是1）检验PARP1 GV发展狼疮的假设和2）测试我们确定的PARP1 SNP与人类链接的PARP1 SNP导致DNA修复受损的假设。为了实现这些目标，我们将产生带有PARP1 GV的小鼠并表征狼疮的发育。我们还将表征该变体在组织培养细胞中的参与DNA RPAIR的能力并表征具有PARP1变体个体的淋巴细胞，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械见解。