Exploring Roles for Transcription Factor Ets1 in Sjogren's Syndrome

探索转录因子 Ets1 在干燥综合征中的作用

基本信息

批准号：
10644080
负责人：
LEE ANN Garrett-Sinha
金额：
$ 17.31万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644080
关键词：
ANCA vasculitis Age Ankylosing spondylitis Antigens Atopic Dermatitis Autoantibodies Autoimmune Autoimmune Diseases Award B-Cell Activation B-Cell NonHodgkins Lymphoma B-Lymphocytes Bioinformatics Biology Bone Marrow Celiac Disease Cells Chimera organism Complement Data Defect Deglutition Dental Development Diagnostic tests Disease ETS1 gene Esthesia Event Foundations Functional disorder Future Gene Expression Genes Genomics Goals Harvest Human Hypergammaglobulinemia Idiopathic Inflammatory Myopathies Immune Immune System Diseases Immune response Immunoglobulin-Secreting Cells Impairment Infiltration Inflammation Inflammatory K-18 conjugate Knockout Mice Laboratories Lacrimal gland structure Learning LoxP-flanked allele Lupus Lymphocyte Mastication Measures Mentors Methods Modeling Molecular Multiple Sclerosis Mus Needs Assessment Oral Pathogenesis Pathology Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Play Predisposition Prevalence Principal Investigator Process Production Property Psoriasis Public Health Reporting Research Research Personnel Rheumatoid Arthritis Risk Role Saliva Salivary Salivary Glands Secondary to Serum Severity of illness Sialadenitis Signal Pathway Sjogren&apos s Syndrome Speech Spleen Structure Structure of germinal center of lymph node Symptoms T-Lymphocyte T-Lymphocyte Subsets Taste Perception Techniques Testing Training Uveitis Vision Xerostomia antimicrobial atopy autoimmune pathogenesis career craniofacial cytokine design experimental study eye dryness genome wide association study immune activation immune function innovation laboratory experience lupus-like lymph nodes meetings migration mouse model new therapeutic target oral infection prevent receptor response salivary cell sex single-cell RNA sequencing training opportunity transcription factor transcriptome

项目摘要

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.

抽象的这是一份 K18 牙科、口腔和颅面科短期指导职业提升奖申请针对职业中期和高级研究人员的研究，重点是确定转录因子的作用使用小鼠模型和基因组学/生物信息学方法进行干燥综合征的 Ets1 培训。该提案的目的是让主要研究者熟悉唾液腺生物和正常功能，并学习表征唾液变化的技术和方法该研究旨在确定是否降低了干燥综合症的水平。 Ets1 促进唾液腺炎症和功能障碍，目前已确定其发挥着重要作用。其他自身免疫性和炎症性疾病，包括狼疮、类风湿性关节炎、牛皮癣、多发性硬化症但在干燥的情况下它是否参与调节免疫功能仍然存在。我们认为 Ets1 调节唾液腺中 B 和 T 淋巴细胞的激活，与此类似。它在脾脏和淋巴结中的功能，并且需要 Ets1 的功能来预防在这个项目中，我们建议检查唾液免疫细胞中的 Ets1 表达。我们进一步研究了干燥综合征模型 NOD.B10 小鼠的腺体，并将其与疾病参数相关联。计划检查缺乏 Ets1 的小鼠，寻找干燥症状的证据，包括浸润到唾液腺，这些实验将导致干燥症中常见的自身抗体的产生和唾液产生的损害。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该提案的导师和共同导师将通过培训 Sjogren 病理学中的潜在作用做出贡献。申请人评估唾液腺功能和发病机制所需的方法以及单- 细胞 RNA 测序以确定唾液腺细胞组成和转录组的变化这些细胞的导师和共同导师都是唾液腺生物学方面的专家，并且拥有以下方面的专业知识：该项目中使用的技术将通过研讨会和会议进行补充。总之，这次培训机会将成为唾液腺生物学和干燥病领域的一个强有力的机会。为 PI 实验室未来干燥病研究奠定基础。