The broad goal of the proposed research is to understand molecular mechanisms of dental renewal and the patterning of complex tooth shapes in regenerating dentitions. The phenomenon of tooth renewal is broadly conserved across vertebrates (i.e., humans replace each tooth once early in life) but is absent in the laboratory mouse. Our research benefits from explicit integration of experimental systems (cichlid fishes, mouse, human) and a unique approach translating new molecular and genetic biology from fishes to mammals and back. Experiments described in Specific Aims 1 and 2 of the research plan use molecular and chemical biology to identify and manipulate cell populations and developmental signaling centers responsible for (i) tooth replacement and (ii) replacement tooth shape. We highlight a novel relationship between teeth and taste buds and exploit the strengths of fish, mouse and human systems to test a model of coordinated organ shape/renewal. Experiments under Specific Aim 3 follow from a new differentiation screen in cichlid fishes to discover novel genes controlling vertebrate replacement tooth shape. Because the genes we identify have not been studied in dentitions before, we use gene targeting in the mouse and molecular biology in humans to explore function. Overall, our collaborative approach is designed to solve problems difficult to study in standard lab models because they either do not replace teeth (mouse) or lack oral teeth altogether (zebrafish, chick). The gaps we aim to fill are significant. One in five humans presents with a genetic disorder affecting the dentition and nearly 100% develop problems (e.g, cavities) with age. 30% of people worldwide over the age of 65 lack teeth entirely. Our proposed research will provide answers to the basic question of how regenerating teeth are partitioned into coordinated zones of renewal and differentiation, as new dental organs develop from their predecessors and cusps form on tooth tips. Insights should promote innovative strategies for bio-inspired regenerative dentistry.

Public Health Relevance

The World Health Organization reports that nearly 100% of people worldwide exhibit dental defects (either genetic disorders or insults acquired with age) and that 30% of those over 65 have none of their 32 teeth remaining. Our research thus explores endogenous mechanisms of tooth regeneration and the patterning of replacement teeth with complex shapes, phenomena shared by most vertebrates including humans but absent in the laboratory mouse. Understanding natural pathways of tooth renewal will galvanize problem solving in bioengineering and may ultimately improve the lives of humans requiring dental implants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019637-05
Application #
8639518
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2009-01-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$604,836
Indirect Cost
$110,836
Name
Georgia Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
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Loh, Yong-Hwee E; Bezault, Etienne; Muenzel, Frauke M et al. (2013) Origins of shared genetic variation in African cichlids. Mol Biol Evol 30:906-17
Fraser, Gareth J; Bloomquist, Ryan F; Streelman, J Todd (2013) Common developmental pathways link tooth shape to regeneration. Dev Biol 377:399-414
Loh, Yong-Hwee E; Yi, Soojin V; Streelman, J Todd (2011) Evolution of microRNAs and the diversification of species. Genome Biol Evol 3:55-65
Fraser, Gareth J; Cerny, Robert; Soukup, Vladimir et al. (2010) The odontode explosion: the origin of tooth-like structures in vertebrates. Bioessays 32:808-17