Laboratory of Kimberly J. Jasmer, PhD
Assistant Professor - Department Oral Immunology & Infectious Diseases
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Summary of research
Research in the Jasmer laboratory focuses on the ways in which immune cells within the inflamed salivary gland communicate with their cellular neighbors. We are interested in understanding the spatial organization and composition of these cellular neighborhoods and how cellular conversations impact disease progression. We focus on cell-cell communication and subsequent downstream signaling processes resulting from receptor binding of lysophospholipids and extracellular nucleotides. Currently, we study these processes in the context of chronic autoimmune Sjögrens Disease (SjD) as well as salivary gland dysfunction that occurs due to head and neck irradiation. Treatments for both diseases primarily focus on symptom management as no FDA-approved curative therapeutics presently exist. Thus, these lines of inquiry aim to identify and validate novel therapeutic targets and translate our findings to the clinic. We utilize a variety of molecular, biochemical, cellular and bioinformatic approaches to explore these fundamental questions about cellular communication and then translate our findings to in vivo preclinical models.
Current projects
P2Y Receptors and Sjögren’s Disease Pathology
Sjögren’s disease (SjD) is a chronic, inflammatory autoimmune disease characterized by lymphocytic infiltration of the lacrimal and salivary glands, resulting in dry eye and dry mouth, respectively. However, it is a systemic disease affecting other exocrine and non-exocrine tissues. Salivary gland hypofunction in SjD increases the incidence of periodontitis, yeast and bacterial infections and digestive disorders. B cells play an essential role in the pathogenesis of SjD, and indicators of B cell hyperactivity in SjD include the production of autoantibodies, hypergammaglobulinemia, and the development of B cell lymphomas. In addition to glandular pathology, SjD patients experience pulmonary manifestations, neurological disorders and hematological conditions. Our studies not only focus on the salivary glands but also on other tissues affected by systemic SjD, such as the lungs, lacrimal glands, and the various tissues where B-cell lymphomas can develop.
Dr. Jasmer’s previous research examined 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. Specifically, her work studied disease processes resulting from activation of the P2Y2 receptor (P2Y2R) on salivary gland-infiltrating B lymphocytes. Currently, her lab, with support from the National Institute of Dental and Craniofacial Research (NIDCR), is investigating the role of the novel P2Y10 receptor (P2Y10R) for Lysophosphatidylserine (LysoPS) in the pathology of SjD.
Salivary Gland Lymphoepithelial Lesions (LELs) and Their Role in Lymphomagenesis
Patients with SjD have a five-fold increased risk of developing non-Hodgkin's lymphoma, particularly extranodal marginal zone (MZ) B cell lymphomas of the mucosa-associated lymphoid tissue (MALT) origin. SjD-associated MALT lymphomas predominantly originate in the parotid salivary glands, though they are also reported in other tissues impacted by SjD, including the lung. SjD-associated MALT lymphoma development is a multi-step process: unorganized infiltrating lymphocytes develop into organized periductal (salivary gland) or peribronchial (lung) lymphoid follicles. Lymphoepithelial lesions (LELs) arise when lymphocytes disrupt these epithelial structures. Evidence suggests that chronic activation of self-reactive marginal zone B cells within the LEL may eventually give rise to marginal zone B cell MALT lymphomas. However, the transition from benign LEL to malignant lymphoma in SjD is poorly understood.
The Jasmer Lab aims to precisely characterize the progression from lymphocytic aggregate to LEL to malignant lymphoma using a preclinical animal model and histological and bioinformatic analyses of human patient samples. The goal is to identify cellular signaling processes and contextualize these within their disease stage based on histological examination.
Identification and Validation of P2Y10 Receptor Modulators Through Virtual Drug Screen and Functional Bioassay
Presently, there are no pharmacological tools available to perform mechanistic studies or modulate P2Y10R function either for the study of this receptor or to test as novel therapeutics. The Jasmer Lab is collaborating with investigators at the UofL Health Brown Cancer Center to identify putative P2Y10R modulators (agonists or antagonists) via virtual drug screen and assess their function using a high-throughput bioassay.
Radiation-Induced Immunomodulation and 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 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 Jasmer lab focuses on the immunomodulatory effect of radiation on the salivary gland, generating a longitudinal landscape of salivary immune profiles at acute and chronic timepoints following RT.
The epithelium plays a significant role in responding to insults and coordinating an immune response. Following irradiation, human and murine epithelial cells release ATP that we have demonstrated in murine parotid salivary gland cells serves to activate the ionotropic P2X7 receptor (P2X7R). Indeed, our work has determined that antagonism or deletion of P2X7R is radioprotective. Ongoing studies supported by the NIDCR in collaboration with the University of Missouri and 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.
Current funding
- Illuminating the Role of the Novel G Protein-Coupled P2Y10 Receptor in Sjögren’s Disease Pathophysiology, National Institute of Dental and Craniofacial Research, R03DE033729 (PI)
- The P2X7 Receptor for ATP as a Therapeutic Target in the Prevention of Radiation-Induced Salivary Gland Dysfunction, National Institute of Dental and Craniofacial Research, R01DE032032 (Co-I)
Publications
Affiliations
- International Association for Dental Research (IADR)
- Salivary Research Group (President Elect)
- IADR Women in Science Network (Member)
- American Association for Dental, Oral, and Craniofacial Research (AADOCR)
- AADOCR Committee on Diversity & Inclusion (Member)