Xaralabos (Bob) Varelas, PhD

Assistant Professor
Boston University School of Medicine
Department of Biochemistry
Boston, MA
Defining Epithelial Cues Contributing to Sjogren’s Syndrome

The Lay Abstract is for publicity purposes and should use simple language summarizing the proposed research and its significance.

Treatments for Sjogren’s syndrome have been limited by our incomplete understanding of the causes and drivers of the disease. The disease is classically characterized as a disorder of the immune system, as inappropriate activation of immune cells that attack mucus secreting organs is observed in patients. Our studies have shown that the cells within affected organs of patients also exhibit structural defects, leading us to hypothesize that these structural defects trigger a chronic immune response, as these cells are recognized as being defective and hence “foreign”. This proposal aims to define the molecular events accompanying the
structural changes that occur in the organs of Sjogren’s syndrome patients, and test whether promoting such defects in animal models leads to similar disease symptoms. Our work offers a new view of how Sjogren’s syndrome arises, which will help define biomarkers of disease progression and offer new targets for therapeutic development.

The Scientific Abstract is written for SSF reviewers and a professional audience.

Although the etiology of of Sjogren’s syndrome (SS) remains unknown, the prevailing model has been that loss of secretory function is a secondary effect of lymphocytic infiltrates. Our studies offer alternative insight, as our observations indicate that aberrant epithelial features may arise independent of the immune response and therefore provides signals that drive SS
development. We propose to test and define whether the pathogenesis of SS arises from the aberrant epithelial integrity. Specifically, we hypothesize that loss of epithelial cell polarity promotes abnormal activation of the Hippo pathway effector Yap, which drives epithelial and stromal changes that elicit an immune response. We will test our hypothesis by characterizing
SS patient tissues, and aligning our observations with analysis of polarity defective mouse models. Our work will therefore provide important molecular insight into dysregulated polarity as a driver of SS phenotypes, offering potential novel therapeutic strategies.