Base Excision Repair and Autoimmunity

描述(申请人提供)：已发现80多种自身免疫性疾病。在美国，自身免疫性疾病被认为影响了1400万至2200万人，其中对女性的影响不成比例。这些疾病给该国的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，但这些疾病中的大多数原因仍然未知。这项拟议研究的长期目标是了解DNA修复异常和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，并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描述我们的小鼠的表型，以便产生可测试的假说，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洞察。其具体目的是鉴定表达Y265C碱基切除修复变异体的小鼠是否存在自身免疫性疾病，验证Y265C小鼠自身免疫性疾病的表现需要B和/或T细胞的假设，以及Y265C小鼠模型中启动DNA氧化损伤修复是自身免疫性疾病的先决条件的假设。为了实现这些目标，我们将定量评估这些小鼠的自身免疫性疾病的症状及其发生的时间。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和/或T细胞，以及氧化DNA损伤是否在自身免疫性疾病中发挥作用。我们研究的意义在于，在编码碱基切除修复功能的酶的基因中，有100多个已知的单核苷酸多态(SNPs)。因此，在氧化代谢存在的情况下，生殖系SNP的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械性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.