Assistant Research Professor
Biochemistry - CAFNR
Research at a glance
Area(s) of Expertise
I study extracellular nucleotides and how they result in signaling processes that influence inflammatory diseases of the salivary glands. Currently, we study these signaling pathways in the chronic autoimmune Sjögrens disease as well as salivary gland dysfunction that occurs due to head and neck irradiation.
The overall goal of my research program is to understand how purinergic receptors orchestrate the immunopathology of salivary gland disorders via extracellular nucleotide sensing and subsequent downstream signaling pathways. Current projects:
NUCLEOTIDE RECEPTORS AND SJÖGRENS DISEASE PATHOLOGY
Sjögren’s disease (SjD) is a chronic, inflammatory autoimmune disease that is characterized by lymphocytic infiltration of the lacrimal and salivary glands, resulting in dry eye and dry mouth, respectively, though it is a systemic disease that also affects other exocrine and non-exocrine tissues. Salivary gland hypofunction in SjD results in an increased incidence of periodontitis, yeast and bacterial infections, and digestive disorders. B cells play an important role in the pathogenesis of SjD and indicators of B cell hyperactivity in SjD include production of autoantibodies, hypergammaglobulinemia, and the development of B cell lymphomas.
We have investigated how the release of cytoplasmic nucleotides from damaged cells, such as adenosine 5’-triphosphate (ATP), acts as an extracellular damage-associated molecular pattern (DAMP) to initiate chronic inflammatory responses through activation of P2 nucleotide receptors, including ATP-gated ionotropic P2X receptors and G protein-coupled P2Y receptors. We’ve previously reported that the G protein-coupled P2Y2 receptor (P2Y2R) is functionally expressed in salivary gland-infiltrating B cells where P2Y2R activation mediates B cell migration and cytokine release. We have also demonstrated that antagonism or genetic deletion of this receptor resolves lymphocytic infiltration of the salivary gland and restores salivary function in multiple mouse models of SjD.
In addition to glandular pathology, SjD patients experience pulmonary manifestations, neurological disorders, and hematological conditions, the most severe of which is the increased risk of developing B-cell lymphomas. Current research in our group is focused on whether P2Y2R or P2X7R antagonism can ameliorate systemic manifestations in SjD mouse models. The long-term goal of this project is to evaluate whether P2Y2R and/or P2X7R antagonism can serve as a novel therapeutic strategy for SjD, where presently no effective therapies exist.
RADIATION-INDUCED SALIVARY GLAND DAMAGE
Following radiotherapy (RT) for the treatment of head and neck cancer (HNC), collateral damage to surrounding tissues, such as salivary glands, is a significant problem. Despite advancements in radiation dosing and delivery, over two-thirds of HNC patients still experience RT-induced xerostomia (i.e., dry mouth), the majority of whom will never regain function. Chronic hypofunction results in changes in saliva quality (e.g., pH, composition, viscosity), increased incidence of dental caries and oral infections, periodontitis, difficulties with swallowing and speaking and nutritional deficiencies, all of which can affect the quality of life for patients. Previous studies in patients receiving RT for HNC have suggested that acute dysfunction results from disruption of acinar epithelial cells that secrete saliva, whereas chronic dysfunction may result from additional factors, such as glandular atrophy, lymphocytic infiltration (i.e., sialadenitis) and periductal and parenchymal fibrosis.
The immunomodulatory effect of RT has been described in multiple contexts, including in thoracic RT, which can result in inflammation of the lung (i.e., pneumonitis) and pulmonary fibrosis. Several mechanisms for this response have been proposed, including activation and proliferation of immune cells, such as dendritic cells, and enhanced chemokine and cytokine release. Previous studies have utilized mouse models of targeted head and neck irradiation to investigate mechanisms of salivary dysfunction, stem cell function and regeneration. However, fewer studies have investigated the immune response in the salivary glands following RT and the contributions of sustained inflammation to chronic dysfunction have not been explored. Targeting the inflammatory response after the acute phase and prior to irreparable glandular damage may be a strategy for preventing chronic hypofunction. To identify potential therapeutics and effective timing for administration, we must first have a more detailed understanding of the immunological processes involved. To this end, thanks to a 2022 Research Council grant, we developed a timeline of the mouse salivary gland immune responses to ionizing radiation (IR).
The epithelium plays a significant role in responding to insults and coordinating an immune response. This interplay between epithelial and immune cells has been reported in models of infection and autoimmune disease of the SG epithelium, i.e., Sjögrens syndrome, and as a result of ionizing radiation. Following irradiation, human and murine cells release ATP that we have demonstrated in murine parotid salivary gland epithelial cells serves to activate the ionotropic P2X7 receptor (P2X7R). We have previously found that antagonism or deletion of P2X7R is radioprotective. Ongoing studies in collaboration with the University of Arizona are elucidating the duration of this radioprotection, the effect on salivary gland immune cells, and the impact on the adjacent tumor during therapy.
The Weisman lab previously reported that activation of P2X7R results in the release of IL-1β, which upregulates the G protein-coupled P2Y2 receptor (P2Y2R), a well-studied mediator of localized immune responses. We hypothesize that IR-induced ATP release causes P2X7R-dependent upregulation of the P2Y2R in salivary gland epithelial and immune cells, whereupon P2Y2R activation by released ATP mediates immune cell recruitment, proliferation, and activation, thereby contributing to long-term inflammation, fibrosis and salivary hypofunction. Thus, in addition to P2X7R, P2Y2R may serve as a more proximal and desirable therapeutic target for preserving salivary function during radiotherapy.
- Ph.D., University of Missouri, 2015
- B.S., University of Washington, 2009