Regenerative medicine represents an exciting new approach in the treatment of human disease. Progress has been made in strategies for the regeneration of a variety of tissues including skin, corneal epithelium, cartilage, bone and bladder. Tissue regeneration would represent an important advancement in the treatment of salivary gland hypofunction that occurs in the autoimmune disease Sj?gren's syndrome and as a result of ?-irradiation therapies for head and neck cancers. To develop techniques for the successful regeneration of salivary glands in vivo, it is first necessary to understand signaling pathways that regulate gland development, which involves acinar formation (i.e., cell proliferation and migration) and organization of acini into a functional gland structure (i.e., cell differentiation into a polarized epithelium with high transepithelial resistance). Towards the goal of regenerating salivary gland tissue, our studies have identified a P2Y2 nucleotide receptor (P2Y2R) that is upregulated in diseased or damaged salivary glands. These published and preliminary findings have demonstrated that P2Y2R activation regulates signaling pathways that mediate cell proliferation and migration and the maintenance of tight junctions required for normal saliva secretion. Over the past 15 years, we have identified novel structural motifs in the P2Y2R that facilitate interactions with complex signaling networks known to regulate cell growth and differentiation involving integrins, growth factor receptors, matrix metalloproteases, adhesion molecules and cytoskeletal proteins. These signaling networks enable the P2Y2R to regulate cellular responses, including migration and proliferation, integrin/extracellular matrix interactions, cytoskeletal rearrangements and the expression of cell adhesion molecules and tight junction proteins. Collectively, these results strongly support the hypothesis that expression and activation of P2Y2Rs in damaged or diseased salivary gland epithelium promote tissue repair and regeneration. Accordingly, we propose to utilize in vitro models of acinar formation to demonstrate that activation of P2Y2Rs enhances regenerative responses. We also will use in vivo submandibular gland (SMG) duct-ligation to validate a role for P2Y2Rs in the recovery and regeneration of damaged salivary glands. We have organized these hypotheses around several Specific Aims.
Specific Aim 1 will identify P2Y2R signaling pathways that mediate acinar formation.
Specific Aim 2 will investigate the role of integrin/P2Y2R interactions in cellular responses required for acinar formation.
Specific Aim 3 will determine whether P2Y2R interaction with the actin cytoskeleton regulates tight junction organization in Par-C10 monolayers. The 3 Specific Aims in this proposal are designed to identify the mechanisms whereby P2Y2R upregulation and activation enhances salivary gland regeneration towards developing better therapies to repair damaged salivary glands.

Public Health Relevance

Salivary glands are damaged by diseases such as Sj?gren's syndrome and as a result of ?-irradiation therapies for head and neck cancers. Our studies have identified a receptor on the cell surface, the P2Y2 nucleotide receptor (P2Y2R) that is upregulated in diseased or damaged salivary glands. Previous studies have demonstrated that P2Y2R activation regulates signaling pathways that mediate cell proliferation, migration and differentiation, which strongly support the hypothesis that expression and activation of P2Y2Rs in damaged or diseased salivary glands can be used to promote tissue repair and regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE007389-25
Application #
8431683
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (02))
Program Officer
Burgoon, Penny W
Project Start
1992-08-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
25
Fiscal Year
2013
Total Cost
$333,656
Indirect Cost
$110,193
Name
University of Missouri-Columbia
Department
Type
Schools of Medicine
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; 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
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
El-Sayed, Farid G; Camden, Jean M; Woods, Lucas T et al. (2014) P2Y2 nucleotide receptor activation enhances the aggregation and self-organization of dispersed salivary epithelial cells. Am J Physiol Cell Physiol 307:C83-96
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
Woods, Lucas T; Camden, Jean M; Batek, Josef M et al. (2012) P2X7 receptor activation induces inflammatory responses in salivary gland epithelium. Am J Physiol Cell Physiol 303:C790-801
Yelovitch, Shir; Barr, Haim M; Camden, Jean et al. (2012) Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y(1) receptor agonist. J Med Chem 55:7623-35
Weisman, Gary A; Woods, Lucas T; Erb, Laurie et al. (2012) P2Y receptors in the mammalian nervous system: pharmacology, ligands and therapeutic potential. CNS Neurol Disord Drug Targets 11:722-38
Weisman, Gary A; Ajit, Deepa; Garrad, Richard et al. (2012) Neuroprotective roles of the P2Y(2) receptor. Purinergic Signal 8:559-78

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