Exploring Roles for Transcription Factor Ets1 in Sjogren's Syndrome

摘要 这是一份K18牙科、口腔和颅面专业短期导师职业提升奖的申请表 专注于确定转录因子的作用的职业中期和高级研究人员的研究 利用小鼠模型和基因组学/生物信息学方法研究干燥综合征中的Ets1。培训中心- 该提案的主要目的是让首席调查员熟悉唾液腺生物- OGY和正常功能，并学习描述唾液变化的技术和方法 腺体对干燥综合征的反应。研究部分试图确定是否减少了 Ets1促进唾液腺炎症和功能障碍。Ets1现在已经确立了扮演重要角色的地位 在其他自身免疫性和炎症性疾病中，包括狼疮，类风湿性关节炎，银屑病，多发性硬化症- SIS和其他人。但在Sjogren遗体的背景下，它是否参与调节免疫功能 未知。我们假设Ets1调节唾液腺中B和T淋巴细胞的激活，类似于 它在脾和淋巴结中的功能以及Ets1的功能是防止肿瘤发展所必需的。 Sjogren的症状。在这个项目中，我们建议检测唾液免疫细胞中Ets1的表达。 干燥综合征模型NOD.B10小鼠的腺体，并与疾病参数相关。我们进一步 计划检查缺乏Ets1的小鼠，以寻找Sjogren症状的证据，包括渗入唾液腺， 干燥症中常见的自身抗体的产生和唾液产生的损害。这些实验将 帮助确定Ets1在调节唾液腺局部免疫反应中的作用，并建立其 在Sjogren的病理中可能起到的作用。本计划的导师和共同导师将通过培训 适用于评估唾液腺功能和发病机制所需的方法，以及使用单项- 细胞RNA测序以确定唾液腺和转录组的细胞组成的变化 这些细胞。导师和共同导师都是唾液腺生物学方面的专家，并在 将在这个项目中使用的技术。本实验室培训将通过研讨会和会议加以补充。 在唾液腺生物学和干燥病领域。总而言之，这次培训机会将是一个强大的 为未来干燥病的实验室研究奠定基础。

Abstract This is a K18 application for a Short-term Mentored Career Enhancement Award in Dental, Oral and Craniofacial Research for Mid-Career and Senior Investigators that focuses on identifying roles for the transcription factor Ets1 in Sjogren’s syndrome using mouse models and genomics/bioinformatics approaches. The training com- ponent of the proposal is designed to allow the principal investigator to become familiar with salivary gland biol- ogy and normal function and to learn the techniques and approaches to characterize changes in the salivary gland in response to the Sjogren’s syndrome. The research component seeks to determine if reduced levels of Ets1 promote salivary gland inflammation and dysfunction. Ets1 is now well-established to play important roles in other autoimmune and inflammatory diseases including lupus, rheumatoid arthritis, psoriasis, multiple sclero- sis and others. But whether it is involved in regulating immune function in the context of Sjogren’s remains unknown. We hypothesize that Ets1 regulates activation of B and T lymphocytes in the salivary gland similar to its functions in spleen and lymph node and that the functions of Ets1 are needed to prevent development of Sjogren’s symptoms. In this project, we propose to examine Ets1 expression in immune cells of the salivary gland in NOD.B10 mice, a model of Sjogren’s syndrome, and correlate it with parameters of disease. We further plan to examine mice lacking Ets1 for evidence of Sjogren’s symptoms including infiltrates into the salivary gland, production of autoantibodies common in Sjogren’s and impairments of saliva production. These experiments will help to define roles for Ets1 in regulating the local immune response in the salivary gland and establish its potential role in Sjogren’s pathology. The mentor and co-mentor of this proposal will contribute by training the applicant in methods needed for assessing salivary gland function and pathogenesis and in the use of single- cell RNA-sequencing to identify changes in the cellular composition of the salivary gland and the transcriptome of those cells. Both the mentor and co-mentor are experts in salivary gland biology and have expertise in the techniques to be used in this project. This laboratory training will be complemented by seminars and meetings in the field of salivary gland biology and Sjogren’s disease. In sum, this training opportunity will serve as a strong foundation for future Sjogren’s disease research in the laboratory of the PI.