Primary Sjögren’s syndrome (pSS) is an autoimmune disease of exocrine tissues causing dry mouth and eyes, mainly affecting women. A culmination of etiologic events leads to the loss of epithelial homeostasis resulting in the MMP9-mediated destruction of the extracellular matrix (ECM). The disease process mainly occurs within the salivary and lacrimal glands and is followed by immune cell infiltration in most cases. Overall, the extent to which the epithelium is involved in the initiation and continuous destruction of glandular structures is supported by a growing body of evidence and is suspected to occur slowly over several years. Inflammatory mediators and immune cell infiltration were historically the suspected drivers of MMP9 mediated ECM destruction. However, both inflammatory and immune responses that affect salivary/lacrimal glands directly, occur later during disease progression, well after ECM degradation and MMP9 overexpression are observed. Herein, I sought to determine factors capable of regulating MMP9 following the evidential pathogenesis and role of the pSS epithelium. Using an innovative bioinformatics approach we identified transcription factors, ETS1 and LEF1, as candidate regulators of MMP9 expression. To substantiate these findings, we first determined whether ETS1 and LEF1 are co-overexpressed with MMP9 in pSS labial salivary gland (LSG) biopsies in lieu of infiltrating CD4+ lymphocytes, which also express these factors in pSS. To fully establish a direct in-vitro regulatory relationship among ETS1, LEF1 and MMP9, I developed two unique, immortalized salivary gland epithelial cell lines from a pSS (FS=1.8) and a non-pSS "sicca complex" (FS=0.3) patient (Chapter 2). Subsequently, I provided substantial evidence using two salivary gland cancer cell lines and iSGEC line models, regarding the direct regulation of MMP9 by ETS1 in the salivary gland epithelium (Chapter 3). After cloning the MMP9 promoter into a luciferase reporter vector, three significant sites responsible for ETS1 binding were validated in vitro. The interaction of ETS1 with the MMP9 promoter was further confirmed by ChIP analysis. ETS1 siRNA mediated knockdown decreased MMP9 mRNA and both intracellular and secreted MMP9 protein levels, overall demonstrating the regulatory effect on MMP9 expression. Taken together, these data suggest that ETS1 regulates MMP9 overexpression in the pSS salivary glands, thereby constituting a significant target for decreasing ECM destruction in pSS, since current MMP9 inhibitors have been proven inadequate. Many etiologic conditions contributing to the development of pSS have been put forth, including an improper telomere maintenance response after DNA damage, which ultimately leads to senescence associated with telomere shortening in salivary progenitor cells within the pSS epithelium. Beyond functional maintenance of the salivary glands, the ECM regulates repair and re-epithelization by salivary progenitor cells. Disruption of the ECM could be a driving factor related to the excessive replication history and shortened telomeres of pSS salivary progenitor cells. To determine a relationship between ETS1, LEF1, and MMP9 expression, we utilized a PCR-based approach to determine relative telomere length. In Chapter 4, I showed that pSS patients had significantly shorter telomeres of saliva DNA compared to healthy controls. Using LSG biopsies of pSS and non-pSS patients, I also determined mRNA overexpression of DNA-damage response mediator, ATM, in pSS patients. These results provided evidence for the impact of DNA damage to the pSS epithelium, suggesting a causal relationship with shortening of salivary telomere DNA, consistent with aging and senescence in peri-menopausal and post-menopausal women. Lastly, telomere shortening significantly correlated with LEF1 expression in LSGs, expanding the relationship between disease activity and expression of previously identified transcription factors. Overall, these data indicate a potential role for LEF1 in telomere-mediated dysfunction and the DNA-damage response within the salivary gland of pSS patients.