Base Excision Repair and Autoimmunity

描述（由申请人提供）：已发现80多种自身免疫性疾病。据认为，自身免疫性疾病在美国影响着1400万至2200万人，其中女性的影响尤为严重。这些疾病给国家卫生保健系统带来了巨大的财政负担。尽管研究已经为自身免疫性疾病带来了重要的新机制见解，但大多数这些疾病的病因仍然未知。该研究的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。我们最近产生了携带Y265C DNA聚合酶β变体的碱基切除修复受损小鼠，发现它们表现出自身免疫性疾病的症状。在这项应用中，我们建议进行实验来定量表征我们小鼠的表型，以产生可测试的假设，其结果有可能为畸变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碱基切除修复变异体的小鼠自身免疫性疾病的存在，验证B细胞和/或T细胞是Y265C小鼠自身免疫性疾病表现所必需的假设，以及验证在Y265C小鼠模型中启动DNA氧化损伤修复是自身免疫性疾病发生的先决条件的假设。为了实现这些目标，我们将定量评估这些小鼠自身免疫性疾病的症状及其发生时间。我们还将产生在Rag1缺陷背景和DNA修复糖基酶缺陷背景下表达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细胞和/或t细胞，以及氧化DNA损伤是否在自身免疫性疾病中起作用。在编码碱基切除修复功能的酶的基因中有超过100个记录的单核苷酸多态性（snp），这一事实突出了我们研究的意义。因此，存在氧化代谢的种系SNP组合可能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的新疗法的发展。

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.