Modeling Sjogrens Syndrome with Id3 Conditional Knockout Mice

用 Id3 条件性基因敲除小鼠模拟干燥综合症

• 批准号: 7460464
• 负责人: Yuan Zhuang
• 金额: $ 23.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460464
• 关键词: Affect; Alleles; Animal Model; Autoimmune Diseases; Biological; Case Study; Cell Lineage; Cells; Chronic; Clinical; Communities; Country; Development; Disease; Disease model; Future; Genetic; Human; Immune; Inflammation; Joints; Kidney; Knock-out; Knockout Mice; Laboratories; Lead; Link; Lung; Modeling; Mus; NIH Program Announcements; National Center for Research Resources; Oral cavity; Organ; Outcome; Pathogenesis; Pathology; Patients; Phenotype; Play; Research; Role; Salivary Glands; Sjogren' s Syndrome; Staging; Syndrome; System; T-Cell Development; T-Lymphocyte; Testing; Woman; Work; base; clinical application; disease phenotype; eye dryness; interest; middle age; mouse model; novel; response; tool

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.

描述（由申请人提供）：干燥综合征是最普遍的风湿性自身免疫性疾病之一，在这个国家影响大约400万人，大多数是中年妇女。这种疾病是由泪腺和唾液腺的慢性炎症引起的，导致持续的眼睛和口腔干燥以及涉及许多其他器官如关节、肾和肺的系统性问题。在我的实验室进行的工作表明，Id 3-/-小鼠发展原发性干燥综合征。这种小鼠模型为进一步了解干燥综合征的病因提供了独特的遗传工具。我们最近对Id 3缺陷小鼠的研究表明，34 T细胞在这种疾病模型中发挥作用。这一新的发现特别有趣，因为在临床病例报告中，干燥综合征中的34个T细胞已经被牵连。我们计划使用Id 3条件等位基因来研究疾病发展中Id 3的谱系和阶段特异性需求。这些研究的结果应该可以建立Id 3在特定发育阶段的特定细胞谱系中的功能与干燥综合征之间的因果关系。34 T细胞参与这种疾病模型，如果被证明是真的，将是特别新颖的，并指出一个新的方向，在临床应用。 相关性：本提案是对国家研究资源中心项目公告（PA-07-336）的回应，该公告呼吁开发动物模型和相关生物材料用于研究。我们计划建立一种新的研究干燥综合征的动物模型，并将此模型提供给科学界进行相关研究。干燥综合征是最普遍的风湿性自身免疫性疾病之一，在这个国家影响大约400万人，其中大多数是中年妇女。这种疾病是由免疫细胞对泪腺和唾液腺的慢性攻击引起的，导致持续的眼睛和口腔干燥。在我的实验室进行的工作表明，Id 3缺陷小鼠发展为原发性干燥综合征。然而，这种动物模型中的疾病机制目前尚不清楚。我们最近的工作导致了一个新的假设，即34 T细胞中Id 3的缺失可能足以引发干燥综合征。为了验证这一假设并建立更明确的动物模型，我们计划建立Id 3条件性敲除小鼠，其仅在34个T细胞中消除Id 3。我们将在这个新的动物模型中评估与干燥综合征相关的表型。