The potential utility of adult stem or progenitor cells for repair of radiation-damaged salivary glands is high, but is currently only a theoretical solutin for patients suffering from xerostomia. There remain several critical obstacles that must be resolved before cell-based therapy for dysfunctional salivary glands can be moved into the clinical arena. These include the identification of appropriate donor cells, the technology for promoting implantation, and direct functional assays to assess the outcomes. We propose to address these issues, using the powerful and well-defined genetic tools available in mice for tracing cell lineages, and cell types. In combination with tunable hydrogel scaffolds, we will use known salivary gland progenitor cells to determine environmental and cellular cues required for their differentiation in vitro and in vivo. The hydrogels will be used to transplant cells into two opposite environments: regenerating atrophic glands, and damaged irradiated glands. The goal is to determine if the use of hydrogels can promote in vivo differentiation of transplanted progenitor cells. To resolve whether the transplanted cells can produce saliva, we propose to generate a mouse model expressing a tagged secretory protein. Because this tool identifies the cellular source of the secretion, it may also prove to be a critical model for evaluating ways to stimulate endogenous regeneration of damaged salivary glands. The successful completion of this project will establish a foundation for subsequent translational research to progress the technology into clinical applications.

Public Health Relevance

This application combines the tools of mouse genetics with recent advances in biomaterial engineering to ask two questions: 1) Can isolated progenitor cell populations be used to reconstitute functional secretory structures in a damaged salivary gland? 2) Does the introduction of progenitor cells into a dysfunctional gland induce endogenous repair and/or secretion? Until these critical questions are resolved, progress toward cell- based replacement therapy in human salivary glands cannot occur. The successful completion of this project may lay the foundation for subsequent translational research to take the developed technology into clinical applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE022949-03
Application #
8685769
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Melillo, Amanda A
Project Start
2012-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Genetics
Type
School of Medicine & Dentistry
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627
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