By discovering the strategies that animals normally use to renew and regenerate their tissues, we can lay a foundation for regenerative approaches in humans. One of the principal long-term goals of my laboratory is to understand mammalian renewal and regeneration by integrating developmental and evolutionary perspectives. To do this, we are using the dentition as a model and are taking advantage of a remarkable property that is found in diverse mammalian species, which is the ability to grow teeth continuously based on the presence of adult stem cells. Despite initial progress, many gaps and challenges in our knowledge remain. We are still in the early stages of understanding how dental stem cells in the incisor epithelium behave, and we know very little about the mesenchymal stem cells. We also have a great deal to learn about how dental stem cells evolved and how they arise in the embryo during development. The overall scope of the research program proposed here will be to contend with these fundamental questions: How do adult stem cells enable the organ to renew? How do the stem cells in teeth respond to environmental influences such as hibernation and force? How did stem cells emerge during evolution of the mammalian dentition? How do progenitor cells in the embryo provide the starting materials for tooth development? Can we target tooth progenitors to cure disease? The impact of our work will be to provide a solid basic science foundation for future regenerative approaches by obtaining deep insight into a system of natural mammalian dental renewal.

Public Health Relevance

Dental decay and tooth loss constitute an important public health issue, and many patients with birth defects have tooth anomalies that require repair. A thorough understanding of the molecular processes that normally drive tooth formation and renewal will provide an important underpinning for biologically-inspired therapies. We propose to use both evolutionary and developmental approaches to achieve a greater understanding of the regulation of stem cell-driven tooth renewal, and in the long run the results from these studies will be useful for repair and regeneration of teeth and other organs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Unknown (R35)
Project #
5R35DE026602-03
Application #
9525137
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Shum, Lillian
Project Start
2016-09-22
Project End
2024-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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Ching, Saunders T; Infante, Carlos R; Du, Wen et al. (2018) Isl1 mediates mesenchymal expansion in the developing external genitalia via regulation of Bmp4, Fgf10 and Wnt5a. Hum Mol Genet 27:107-119
Herrero, Diego; Cañón, Susana; Pelacho, Beatriz et al. (2018) Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction. Arterioscler Thromb Vasc Biol 38:2160-2173
Castillo-Azofeifa, David; Seidel, Kerstin; Gross, Lauren et al. (2018) SOX2 regulation by hedgehog signaling controls adult lingual epithelium homeostasis. Development 145:
Nguyen, Minh Binh; Cohen, Idan; Kumar, Vinod et al. (2018) FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells. Nat Commun 9:2333
Sanz-Navarro, Maria; Seidel, Kerstin; Sun, Zhao et al. (2018) Plasticity within the niche ensures the maintenance of a Sox2+ stem cell population in the mouse incisor. Development 145:
Calamari, Zachary T; Hu, Jimmy Kuang-Hsien; Klein, Ophir D (2018) Tissue Mechanical Forces and Evolutionary Developmental Changes Act Through Space and Time to Shape Tooth Morphology and Function. Bioessays 40:e1800140
Wald, Tomas; Spoutil, Frantisek; Osickova, Adriana et al. (2017) Intrinsically disordered proteins drive enamel formation via an evolutionarily conserved self-assembly motif. Proc Natl Acad Sci U S A 114:E1641-E1650
Prochazkova, Michaela; Häkkinen, Teemu J; Prochazka, Jan et al. (2017) FGF signaling refines Wnt gradients to regulate the patterning of taste papillae. Development 144:2212-2221
Zheng, X; Goodwin, A F; Tian, H et al. (2017) Ras Signaling Regulates Stem Cells and Amelogenesis in the Mouse Incisor. J Dent Res 96:1438-1444

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