Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral health. It has been estimated that more than 5 million people in the US suffers from salivary gland dysfunction (Sjogren's syndrome). Although no genes mutations have been identified that could explain the pathogenesis of Sjogren's syndrome (SS), recent evidence have suggested that T17-cell infiltration and induction of apoptosis in salivary gland acinar cells could be the two major events that could lead to salivary gland destruction. However, the molecular mechanism involved in the activation of T cells and apoptosis of salivary acinar cells is not known. Interestingly, similar to other autoimmune diseases, females have been shown to be affected with SS more than their male counterparts, with greater than 90% of SS cases being diagnosed in women. One hypothesis to explain this gender difference is that loss of random X-chromosome inactivation could be the cause of this disease (since many genes involved in immune function are expressed on the X- chromosome); however, the reason for the loss of X-chromosome inactivation is not known in any autoimmune disease, including SS. Results obtained from our ongoing studies indicate that a series of key epigenetic changes are observed in SS patients. As a result transcription of a set of genes that are essential for controlling proper immune response may be decreased. In addition, loss of expression of XIST1 (that is critical for random X-chromosome inactivation) may lead to the activation of certain genes on the X- chromosome that increases T cell activation, and initiates apoptosis. Furthermore, most of the loss of methylation on the X-chromosome was found in the CpG islands, which could lead to chromosomal instability and loss of imprinting. To further understand the mechanism, we performed a global RNA seq analysis on control and SS samples and have identified that a master regulator gene ELF4 that is present on the X- chromosome was upregulated (due to loss of X-chromosome inactivation) and could assist in the pathology of SS. These results are novel, and suggest a strong epigenetic origin for SS, but they need to be further validated. Therefore, in this grant proposal we intend to thoroughly characterize the role of epigenetic changes in salivary gland destruction and to determine the relationship between abnormal methylation and X- chromosome inactivation. The hypothesis of this study is that epigenetic changes along with the loss of X- chromosome inactivation alters ELF4 that increases susceptibility to immune changes and promote apoptosis of acinar cells, thereby leading to salivary gland destruction. Thus, identification of the mechanism as well as the pathways that lead to salivary gland destruction could represent as drug targets in salivary gland dysfunction. We will coordinate our efforts in order to determine the functional significance of inhibiting epigenetic changes in order to protect against salivary gland destruction. The results of our studies are expected to provide new insights into the role of epigenetic changes and the molecular mechanism involved in salivary gland destruction. Greater understanding of these events will be important in elucidating new therapy for salivary gland dysfunctions and Sjgerns patients.

Public Health Relevance

It has been estimated that more than 5 million people in the US suffer from salivary gland dysfunctions. Loss of salivary gland function is a limiting side-effect of numerous drugs, serious consequences of head and neck cancer treatment using radiation therapy, and also a frequent outcome of autoimmune diseases such as Sjgerns syndrome. Our current studies are focused on the identification of key epigenetic changes and to establish their role in modulating salivary gland destruction. We anticipate that elucidating the mechanism of epigenetic-induced salivary gland destruction; will be important to understand the pathology present in Sjgerns syndrome. Furthermore, we will identify the mechanism involved in regulating certain genes that are critical in salivary gland destruction per se. Greater understanding of these events will be important in elucidating new therapies for salivary gland dysfunctions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE022765-01A1
Application #
9250480
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chander, Preethi
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of North Dakota
Department
Biochemistry
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202