Salivary gland dysfunction affects millions of Americans whose quality of life is severely impacted by dry mouth, oral bacterial infections, poor nutrition, and other disorders that are associated with decreased saliva production. Loss of saliva production is most common in Sjgren's syndrome (SS), an autoimmune exocrinopathy of unknown etiology in which decreased saliva production is followed by lymphocytic infiltration of the salivary gland and ultimately tissue degeneration. In addition, salivary gland inflammation and hyposalivation is an unintended side effect of ?-radiation used for the treatment of head and neck cancers. Understanding the mechanisms underlying early events in salivary gland inflammation will help identify currently-unavailable therapeutic options to treat salivary gland degeneration. It is now well recognized that high levels of intracellular nucleotides, particularly ATP, are released from cells under pathological conditions in response to inflammation, stress or trauma. Our research has focused on understanding the ATP- dependent mechanisms involved in salivary gland inflammation and degeneration. Recent work by our group indicates that salivary gland inflammation can be initiated by activation of the P2X7 receptor (P2X7R), an ATP- gated, non-selective cation channel that also promotes inflammation and cell apoptosis in several chronic diseases, including rheumatoid arthritis, lung fibrosis, and neurodegenerative and inflammatory bowel diseases. Preliminary studies presented in this proposal indicate that neutrophil recruitment to duct-ligated submandibular gland (SMG) is significantly reduced in P2X7R-/- mice compared to control mice when the glands were perfused with BzATP, a high affinity P2X7R ligand that we initially developed. Therefore, we will utilize primary isolated salivary gland cells and the duct ligation model of salivary gland inflammation in wild type and P2X7R-/- mice to elucidate whether inflammatory responses associated with the P2X7R play a significant role in functional SMG degeneration and the mechanisms involved (Specific Aim 1). Other studies will extend these results to mouse models of radiation-induced salivary gland damage (Specific Aim 2) and autoimmune exocrinopathy (Specific Aim 3), where the availability of the P2X7R-/- mouse and P2X7R-selective antagonists (currently in clinical trials for the treatment of rheumatoid arthritis and spinal cord injury) will enable us to directly examine whether decreases in P2X7R function in vivo can retard salivary gland degeneration. Thus, the overall goal of these studies is to evaluate whether inhibition of P2X7R activity can protect the salivary gland from various forms of tissue damage in mice, which ultimately will be essential for developing treatments for human salivary dysfunction.

Public Health Relevance

Salivary gland dysfunction affects millions of Americans whose quality of life is severely impacted by dry mouth, oral bacterial infections, poor nutrition, and other disorders that are associated with decreased saliva production. Our research focuses on a cell surface P2X7 receptor (P2X7R) for extracellular ATP, the chemical form of energy in a cell that when released from injured or diseased salivary gland tissue causes inflammation. The overall goal of these studies is to evaluate whether deletion or inhibition of the P2X7R can protect the salivary gland from various forms of tissue damage in mice, which ultimately will be essential for developing treatments for human salivary dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE023342-01A1
Application #
8630757
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
2013-12-17
Project End
2018-11-30
Budget Start
2013-12-17
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$590,608
Indirect Cost
$185,096
Name
University of Missouri-Columbia
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Kayes, Timothy Daniel; Weisman, Gary A; Camden, Jean M et al. (2016) New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland. J Immunol 197:2119-30
Woods, Lucas T; Ajit, Deepa; Camden, Jean M et al. (2016) Purinergic receptors as potential therapeutic targets in Alzheimer's disease. Neuropharmacology 104:169-79
Dissmore, Tixieanna; Seye, Cheikh I; Medeiros, Denis M et al. (2016) The P2Y2 receptor mediates uptake of matrix-retained and aggregated low density lipoprotein in primary vascular smooth muscle cells. Atherosclerosis 252:128-35
Sathanoori, Ramasri; Bryl-Gorecka, Paulina; Müller, Christa E et al. (2016) P2Y2 receptor modulates shear stress-induced cell alignment and actin stress fibers in human umbilical vein endothelial cells. Cell Mol Life Sci :
Woods, Lucas T; Camden, Jean M; El-Sayed, Farid G et al. (2015) Increased Expression of TGF-β Signaling Components in a Mouse Model of Fibrosis Induced by Submandibular Gland Duct Ligation. PLoS One 10:e0123641
Weisman, Gary A (2014) Why do male mice spit soluble enzymes that hydrolyze extracellular nucleotides? Focus on "Prostatic acid phosphatase is the main acid phosphatase with 5'-ectonucleotidase activity in the male mouse saliva and regulates salivation". Am J Physiol Cell Physiol 306:C997-8
Liao, Zhongji; Cao, Chen; Wang, Jianjie et al. (2014) The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells. J Biomed Sci Eng 7:1105-1121
Nadel, Yael; Lecka, Joanna; Gilad, Yocheved et al. (2014) Highly potent and selective ectonucleotide pyrophosphatase/phosphodiesterase I inhibitors based on an adenosine 5'-(α or γ)-thio-(α,β- or β,γ)-methylenetriphosphate scaffold. J Med Chem 57:4677-91