Base Excision Repair and Autoimmunity

碱基切除修复和自身免疫

基本信息

批准号：
8431731
负责人：
Joann B. Sweasy
金额：
$ 20.79万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8431731
关键词：
Affect African American Antigens Arthritis Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Base Excision Repairs Biochemical Cell Respiration Cells Characteristics Code Country DNA DNA Damage DNA Polymerase beta DNA Repair DNA-Directed DNA Polymerase Dermatitis Development Disease Environment Environmental Carcinogens Enzymes Exhibits Exposure to Functional RNA Generations Genes Genetically Engineered Mouse Glomerulonephritis Goals Healthcare Systems Immunoglobulin G Knock-out Lead Lupus Metabolism Monitor Mus Nature Nucleotides Outcome Oxygen Phenotype Play Process Rag1 Mouse Reactive Oxygen Species Research Role Serum Single Nucleotide Polymorphism Symptoms System T-Lymphocyte Testing Time Variant Woman base disease characteristic insight metaplastic cell transformation mouse model novel oxidative DNA damage public health relevance repaired research study tissue/cell culture

项目摘要

DESCRIPTION (provided by applicant): More than 80 autoimmune diseases have been identified. Autoimmune diseases are thought to affect 14-22 million people in the US and disproportionately affect women. These diseases impart a significant fiscal burden to the country's health care system. Although research has lead to significant new mechanistic insights for autoimmune diseases, the causes of the majority of these diseases remain unknown. The broad long-term objective of the proposed research is to understand the relationship between aberrant DNA repair and autoimmune disease. We have recently generated base excision repair compromised mice carrying the Y265C DNA polymerase beta variant, and found that they exhibit symptoms of autoimmune disease. In this application, we propose to perform experiments to quantitatively characterize the phenotypes of our mice in order to generate testable hypotheses, the outcomes of which have the potential to provide important mechanistic insight into the role of aberrant DNA repair in autoimmunity. The specific aims are to characterize mice expressing the Y265C base excision repair variant for the presence of autoimmune disease, to test the hypothesis that B and/or T cells are required for the manifestation of autoimmune disease in the Y265C mice, and to test the hypothesis that initiation of the repair of oxidative DNA damage is a prerequisite for autoimmune disease in the Y265C mouse model. To accomplish these goals we will quantitatively assess the symptoms of autoimmune disease in these mice, and their time to occurrence. We will also generate mice expressing the Y265C variant in a Rag1 deficient background and in a DNA repair glycosylase deficient background and assess disease symptoms and time to occurrence in order to determine if B and/or T-cells are required for disease and if oxidative DNA damage plays a role in autoimmune disease. The significance of our studies is highlighted by the fact that there are over 100 documented Single Nucleotide Polymorhisms (SNPs) in genes encoding enzymes that function in base excision repair. Thus, a combination of a germline SNP in the presence of oxidative metabolism could result in autoimmune disease. Furthermore, the mechanistic insights gained in our studies of aberrant DNA repair and autoimmunity are likely to lead to the development of novel therapies for autoimmune diseases.

描述（由申请人提供）：已鉴定出 80 多种自身免疫性疾病。据认为，美国有 14-2200 万人患有自身免疫性疾病，其中女性尤甚。这些疾病给该国的医疗保健系统带来了沉重的财政负担。尽管研究对自身免疫性疾病产生了重要的新机制见解，但大多数这些疾病的原因仍然未知。拟议研究的广泛长期目标是了解异常 DNA 修复与自身免疫性疾病之间的关系。我们最近培育了携带 Y265C DNA 聚合酶 β 变体的碱基切除修复受损小鼠，并发现它们表现出自身免疫性疾病的症状。在此应用中，我们建议进行实验来定量表征小鼠的表型，以产生可检验的假设，其结果有可能为异常 DNA 修复在自身免疫中的作用提供重要的机制见解。具体目的是表征表达 Y265C 碱基切除修复变体的小鼠是否存在自身免疫性疾病，检验 Y265C 小鼠中表现自身免疫性疾病需要 B 和/或 T 细胞的假设，并检验该假设在 Y265C 小鼠模型中，氧化 DNA 损伤修复的启动是自身免疫性疾病的先决条件。为了实现这些目标，我们将定量评估这些小鼠的自身免疫性疾病的症状及其发生时间。我们还将在 Rag1 缺陷背景和 DNA 修复糖基化酶缺陷背景中生成表达 Y265C 变体的小鼠，并评估疾病症状和发生时间，以确定疾病是否需要 B 和/或 T 细胞以及氧化 DNA 是否需要损伤在自身免疫性疾病中发挥作用。我们研究的重要性在于，在编码具有碱基切除修复功能的酶的基因中，有超过 100 个已记录的单核苷酸多态性 (SNP)。因此，在氧化代谢存在的情况下，种系 SNP 的组合可能会导致自身免疫性疾病。此外，我们在异常 DNA 修复和自身免疫研究中获得的机制见解可能会导致自身免疫性疾病新疗法的开发。