The amelogenin proteins have a fundamental role in development of normal dental enamel. Evidence for this comes from patients with mutations in the amelogenin (AMELX) gene, who have the enamel defect amelogenesis imperfecta (AI), and from Amelx null mice, which have a condition similar to the X-linked form of AI. Null and transgenic murine models that correspond to various types of AI identified in human patients have begun to reveal roles of both the normal and mutated enamel proteins. Mice null for matrix metalloproteinase-20 (MMP-20) also have an enamel defect similar to a human AI, due to deficiency in proteolytic processing of amelogenins and other enamel proteins during development. These animal models provide information concerning basic processes in human development because of similarities between rodent and human enamel proteins, mineral and dental development in general. In this competitive renewal application, we propose the following aims: (i) To analyze the rescued enamel phenotype in transgenic mice with an Amelx null genomic mutation to determine roles of the 180 and 59 amino acid amelogenin proteins, using light, scanning and transmission electron microscopy;(ii) To evaluate enamel thickness, structure and crystal dimensions and orientation in the Amelx null, MMP20 null, and Amelx null mice with normal and mutated amelogenin transgenes for fundamental information about the role of the amelogenin C-terminus in vivo;(iii) To determine the role of genetic background in the observed enamel phenotypic heterogeneity in null mice;and (iv) To use murine models with different classifications of enamel defects in an interdisciplinary approach to develop enamel bonding treatments for AI in patients with different enamel gene mutations. At the conclusion of this work, a better understanding of the function of individual amelogenins during enamel development, and insight into the role that other proteins play in disease severity, will lead to new treatments designed for individuals with different AI mutations. This combination of basic and clinical approaches will generate fundamental knowledge as well as translational application that will benefit the public by providing therapeutic approaches that correspond to genetic alterations, leading to improved dental/oral health. Project Narrative: Patients with defective enamel frequently have prolonged clinical treatment, pain and social anxiety because of the appearance of their teeth. An understanding of how inherited gene mutations cause enamel defects will lead to insight into how enamel develops and shed more light on how to prevent structural defects from developing. Mouse models mimic the human defects and can be used to correlate individual gene mutations with appropriate clinical intervention. Project Narrative Patients with defective enamel frequently have prolonged clinical treatment, pain and social anxiety because of the appearance of their teeth. An understanding of how inherited gene mutations cause enamel defects will lead to insight into how enamel develops and shed more light on how to prevent structural defects from developing. Mouse models mimic the human defects and can be used to correlate individual gene mutations with appropriate clinical intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011089-14
Application #
8208189
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (09))
Program Officer
Wan, Jason
Project Start
1995-06-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
14
Fiscal Year
2012
Total Cost
$397,102
Indirect Cost
$108,716
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Pugach, Megan K; Ozer, Fusun; Mulmadgi, Raj et al. (2014) Shear bond strength of dentin and deproteinized enamel of amelogenesis imperfecta mouse incisors. Pediatr Dent 36:130-6
Xue, Hui; Li, Yong; Everett, Eric T et al. (2013) Ameloblasts require active RhoA to generate normal dental enamel. Eur J Oral Sci 121:293-302
Li, Yong; Konicki, William S; Wright, J Timothy et al. (2013) Mouse genetic background influences the dental phenotype. Cells Tissues Organs 198:448-56
Gibson, Carolyn W (2011) The Amelogenin Proteins and Enamel Development in Humans and Mice. J Oral Biosci 53:248-256
Pugach, M K; Ozer, F; Li, Y et al. (2011) The use of mouse models to investigate shear bond strength in amelogenesis imperfecta. J Dent Res 90:1352-7
Chen, Xu; Li, Yong; Alawi, Faizan et al. (2011) An amelogenin mutation leads to disruption of the odontogenic apparatus and aberrant expression of Notch1. J Oral Pathol Med 40:235-42
Li, Yong; Pugach, Megan K; Kuehl, Melissa A et al. (2011) Dental enamel structure is altered by expression of dominant negative RhoA in ameloblasts. Cells Tissues Organs 194:227-31
Lindemeyer, Rochelle G; Gibson, Carolyn W; Wright, Timothy J (2010) Amelogenesis imperfecta due to a mutation of the enamelin gene: clinical case with genotype-phenotype correlations. Pediatr Dent 32:56-60
Zhang, Hai; Tompkins, Kevin; Garrigues, Jacques et al. (2010) Full length amelogenin binds to cell surface LAMP-1 on tooth root/periodontium associated cells. Arch Oral Biol 55:417-25
Pugach, M K; Li, Y; Suggs, C et al. (2010) The amelogenin C-terminus is required for enamel development. J Dent Res 89:165-9

Showing the most recent 10 out of 33 publications