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Principal Investigator: Blake Warner
Organization: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Fiscal Year: 2024
Award: $1,642,409
Funding agency: National Institute of Dental and Craniofacial Research
Natural history and pathogenesis of Sjogren's syndrome(SS)
The primary objective of this study is to enable the collection of longitudinal clinical and laboratory data and biologic specimens to identify pathogenetic mechanisms of SS and other salivary gland dysfunction clinical states by careful clinical phenotyping of SS patients and Sjogrens-like conditions over time and collection of biologic samples for concurrent and future laboratory studies related to the pathogenesis of Sjgrens syndrome. Another objective of the study is to identify biomarker candidates associated with the diagnosis, severity, prognosis, or organ involvement in SS.
Associated research projects:
1. Ex-vivo salivary gland functional imaging
The molecular mechanisms underlying salivary gland secretory defects in SS is unknown. While the destruction of glandular structure can contribute to the decrease in total salivary fluid secretion, it does not explain the loss of secretion in patients who have low, or negligible, levels of inflammation in the glands (this group constitutes over 80% of the SS patients).
By obtaining fresh minor salivary gland biopsies from SS patients and healthy volunteers, we examine single acinar cell function from intact acinar clusters, with confocal microscopy.
We are able to measure calcium influx and release in individual cells and also measure individual cell volume changes after agonist stimulation. This has allowed us to focus on specific candidate proteins that might be responsible for the salivary gland dysfunction associated with SS
2.Trancriptome profiling of salivary glands in SS and other salivary gland dysfunction states.
There is an unmet need to characterize the molecular profile of the broad range of phenotypes in SS. With the advent of high throughput sequencing methods, a complete characterization of whole transcriptome of salivary glands and specifically of each of their resident cells types will greatly facilitate the sub-classification and better characterization of the genetic changes in SS patients.
In SS the presence of different levels of inflammation in glands of patients present a challenge when whole glands are used as source of material. Under these circumstances, the analysis of genetic material and proteins from heterogeneous tissue sample as a whole, might mask the important changes that occur in the individual types of cells. Laser capture microdissection allows the procurement of specific cell types by dissecting out only cells of interest.
We are planning to use parotid and minor salivary glands of SS patients and through laser capture microdissection isolate and characterize the genetic profile of ductal and acinar cells as well as the resident lymphocytes . Through this project proteins will also be isolated from each cell type and stored for future
3. Characterization of Immune Checkpoint Inhibition induced sicca
Immunotherapy has provided a needed breakthrough in cancer therapy for a number of malignancies. Immune checkpoint inhibition in some patients leads to durable tumor rejection and increased survival. However, augmenting the immune system can have devastating effects on a number of organ systems. Approximately 25% of patients on drugs targeting the PD-1/PD-L1 co-receptors will experiences severe dry mouth. We are currently investigating the local immune activation in the context of immunotherapy in the salivary gland to gain meaningful mechanistic insight into immune related adverse events duet to immune checkpoint inhibition and rational targets for prevention and treatment.
4. Identify the role of the mouth, and specifically the Salivary Glands, in COVID-19 pathogenesis (Huang, Perez, et al., 2021. Nature Medicine).
Terms: <Acinar Cell><Aciner Cells><Address><Affect><Agonist><Area><Asialia><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Autonomic nervous system><Biological><Biology><Biopsy><Body System><Body Tissues><Buccal Cavity><Buccal Cavity Head and Neck><COVID-19 pathogenesis><COVID19 pathogenesis><Calcium><Cancer Treatment><Cancers><Cavitas Oris><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell Volumes><Cells><Cellular Function><Cellular Physiology><Cellular Process><Checkpoint inhibitor><Classification><Clinic><Clinical><Clinical Data><Clinical Evaluation><Clinical Research><Clinical Study><Clinical Testing><Collaborations><Collection><Complex><Confocal Microscopy><Data><Defect><Development><Diagnosis><Disease><Disorder><Drug Targeting><Ductal Cell><Ductal Epithelial Cell><Dysfunction><Endocrinology><Epithelial Cells><Fluids and Secretions><Functional Imaging><Functional disorder><Future><Gene Modified><Gene Transcription><Genetic><Genetic Alteration><Genetic Change><Genetic Materials><Genetic Transcription><Genetic analyses><Genetic defect><Gland><Goals><Health><High-Throughput Nucleotide Sequencing><High-Throughput Sequencing><Hyposalivation><Iatrogenesis><Immune Cell Activation><Immune checkpoint inhibitor><Immune mediated therapy><Immune system><Immunologically Directed Therapy><Immunology><Immunotherapy><Individual><Inflammation><Investigation><Laboratories><Laboratory Study><Lymphatic cell><Lymphocyte><Lymphocytic><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Masks><Measures><Medicine><Metabolism and Endocrinology><Methods><Minor Salivary Glands><Minor salivary gland structure><Molecular Fingerprinting><Molecular Profiling><Mouth><Mouth Dryness><Mutation><Natural History><Nature><Oral cavity><Organ><Organ System><Orphan Disease><Outcome><PD-1/PD-L1><PD-1/PDL1><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><Parotid><Parotid Gland><Pathogenesis><Pathogenicity><Pathologic><Pathway interactions><Patients><Phenocopy><Phenotype><Physiologic Imaging><Physiopathology><Prevention><Prognosis><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Rare Diseases><Rare Disorder><Receptor Protein><Research><Research Grants><Research Project Grants><Research Projects><Research Specimen><Role><Salivary><Salivary Gland Diseases><Salivary Glands><Salivary Glands Head and Neck><Sampling><Scientist><Severities><Sicca Syndrome><Sjogren's Syndrome><Sjogrens><Sjögren Syndrome><Source><Specialty><Specimen><Structure><Subcellular Process><Syndrome><Systematics><T-Cell Subsets><T-Lymphocyte Subsets><Therapeutic><Time><Tissue Sample><Tissues><Transcription><Variant><Variation><Xerostomia><anti-cancer therapy><aptyalism><autoimmune condition><autoimmune disorder><autoimmunity disease><biologic><biomarker identification><cancer therapy><cancer-directed therapy><candidate biomarker><candidate marker><cell type><check point inhibition><checkpoint inhibition><clinical phenotype><clinical test><coronavirus disease 2019 pathogenesis><coronavirus disease-19 pathogenesis><design><designing><developmental><dry mouth><experience><gene modification><genetic analysis><genetically modified><genome mutation><global gene expression><global transcription profile><healthy volunteer><iatrogenic><iatrogenically><iatrogenicity><identification of biomarkers><identification of new biomarkers><immune activation><immune check point inhibition><immune check point inhibitor><immune checkpoint inhibition><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immune-mediated adverse events><immune-related adverse effect><immune-related adverse events><immune-related adverse reaction><immuno therapy><immunopathology><improved><insight><interest><laser capture microdissection><lymph cell><malignancy><marker identification><medical specialties><molecular imaging><molecular profile><molecular signature><molecule imaging><neoplasm/cancer><new drug treatments><new drugs><new marker><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel biomarker><novel drug treatments><novel drugs><novel marker><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><orphan disorder><pathophysiology><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><physiological imaging><receptor><research clinical testing><salivary cell><salivary disorder><salivary gland disorder><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><transcriptome><transcriptome sequencing><transcriptomic sequencing><tumor><xerodermosteosis>