Exploring Roles for Transcription Factor Ets1 in Sjogren's Syndrome

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.