Base Excision Repair and Autoimmunity

描述（由申请人提供）：已经确定了80多种自身免疫性疾病。据信，自身免疫性疾病影响了美国1400万至2200万人，其中女性的影响尤为严重。这些疾病给国家的保健系统带来了沉重的财政负担。尽管研究已经导致了对自身免疫性疾病的重要的新机制见解，但大多数这些疾病的原因仍然未知。这项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Y265 C 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。在本申请中，我们建议进行实验，以定量表征我们的小鼠的表型，以产生可检验的假设，其结果有可能提供重要的机制洞察异常DNA修复在自身免疫中的作用。具体目的是表征表达Y265 C碱基切除修复变体的小鼠是否存在自身免疫性疾病，以检验B和/或T细胞是Y265 C小鼠中自身免疫性疾病表现所需的假设，并检验氧化DNA损伤修复的启动是Y265 C小鼠模型中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中自身免疫性疾病的症状及其发生时间。我们还将产生在Rag 1缺陷背景和DNA修复糖基化酶缺陷背景中表达Y265 C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起作用。我们的研究的意义是突出的事实，有超过100个记录的单核苷酸多态性（SNP）的基因编码的酶，在碱基切除修复功能。因此，在存在氧化代谢的情况下生殖系SNP的组合可能导致自身免疫性疾病。此外，在我们对异常DNA修复和自身免疫的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.