Modeling Sjogrens Syndrome with Id3 Conditional Knockout Mice

描述(申请人提供)：Sj“gren‘s综合征是风湿性自身免疫性疾病中最常见的一种，在这个国家大约有400万人，其中大部分是中年妇女。这种疾病是由泪腺和唾液腺的慢性炎症引起的，导致眼睛和口腔持续干燥，以及涉及关节、肾脏和肺等许多其他器官的全身性问题。我的实验室所做的工作表明，ID3-/-小鼠会患上原发性的Sj”gren’s综合征。这个小鼠模型为进一步了解干燥综合征的病因提供了一个独特的遗传工具。我们最近对ID3缺陷小鼠的研究表明，34个T细胞在这种疾病模型中发挥了作用。这一新的发现特别有趣，因为临床病例报告中涉及到干燥综合征的34个T细胞。我们计划使用ID3条件等位基因来研究ID3在疾病发展中的谱系和阶段特异性需求。建议的研究结果应该确定ID3在特定发育阶段的特定细胞谱系中的功能与Sj“gren综合征之间的因果联系。34T细胞参与这一疾病模型，如果被证明是真的，将是特别新颖的，并为临床应用指明了新的方向。相关性：这项建议是对国家研究资源中心的计划公告(PA-07-336)的回应，该计划呼吁开发用于研究的动物模型和相关生物材料。我们计划建立一种新的研究干燥综合征的动物模型，并将该模型提供给科学界进行相关研究。干燥综合征是风湿性自身免疫性疾病中最常见的疾病之一，在这个国家大约有400万人，其中大多数是中年妇女。这种疾病是由免疫细胞慢性攻击泪腺和唾液腺导致眼睛和口腔持续干燥引起的。我的实验室的研究表明，ID3基因缺陷的小鼠患上了原发性干燥综合征。然而，该动物模型的发病机制目前尚不清楚。我们最新的工作导致了一个新的假设，即34个T细胞中ID3的缺失可能足以引发Sj“gren综合征。为了验证这一假设并建立更明确的动物模型，我们计划创建ID3条件性基因敲除小鼠，它可以唯一地消除34个T细胞中的ID3。我们将在这个新的动物模型中评估与Sj”gren综合征相关的表型。

DESCRIPTION (provided by applicant): Sj"gren's syndrome is one of the most prevalent rheumatic autoimmune disease affecting approximately 4 million people in this country, mostly women reaching middle age. The disease is caused by chronic inflammation of the lachrymal and salivary glands, resulting in persistent dry eyes and mouth and systemic problems involving many other organs such as joints, kidney, and lung. Work carried out in my laboratory demonstrated that Id3-/- mice develop primary Sj"gren's syndrome. This mouse model provides a unique genetic tool for further understanding the cause of Sj"gren's syndrome. Our most recent studies of Id3 deficient mice indicate that 34 T cells play a role in this disease model. This novel finding is particularly interesting given that 34 T cells in Sj"gren's syndrome have been implicated in clinical case reports. We plan to use an Id3 conditional allele to investigate lineage and stage specific requirement of Id3 in disease development. Results from the proposed studies should establish a causal link between function of Id3 in specific cell lineage at specific stage of development and Sj"gren's syndrome. The involvement of 34 T cell in this disease model, if proves to be true, would be particularly novel and point to a new direction in clinical applications. RELEVANCE: This proposal is in response to the program announcement (PA-07-336) from National Center for Research Resources, which calls for Development of Animal Models and Related Biological Materials for Research. We plan to build a new animal model for studying Sj"gren's syndrome and make this model available for scientific community for relevant research. Sj"gren's syndrome is one of the most prevalent rheumatic autoimmune disease affecting approximately 4 million people in this country, mostly women reaching middle age. The disease is caused by chronic attack of the lachrymal and salivary glands by immune cells resulting in persistent dry eyes and mouth. Work carried out in my laboratory demonstrated that Id3 deficient mice develop primary Sj"gren's syndrome. However, the disease mechanism in this animal model is currently unknown. Our most recent work led to a new hypothesis that loss of Id3 in 34 T cells may be sufficient to initiate Sj"gren's syndrome. To test this hypothesis and to build a more defined animal model, we plan to create Id3 conditional knockout mouse which eliminates Id3 exclusively in 34 T cells. We will assess phenotypes relevant to Sj"gren's syndrome in this new animal model.