Proteomics and Genetics of Enamel and Dentin: Our goals are: a) to isolate and characterize proteins in the enamel and dentin matrices of developing teeth. b) to discover mutations in defective genes that cause dental disorders, and A proteomics approach is proposed to isolate and characterize proteins normally expressed during tooth formation. By discovering novel dentin and enamel matrix proteins, we will identify new candidate genes in the etiologies of inherited dental disorders, such as ame/ogenesis imperfecta (AI) and dentinogenesis imperfecta (DGI).
Two Specific Aims are proposed: SA:1 Isolate and characterize molecules in the extracellular matrices of developing enamel and dentin; and dentin. SA 2: Identify genes and mutations that cause amelogenesis imperfecta and dentinogenesis imperfecta.
In Specific Aim 1 we perform a comprehensive isolation and characterization of the protein components in developing enamel and dentin. Complete resolution of virtually every soluble matrix protein is achieved using a two-dimensional method that separates proteins first by isoelectric point and second by hydrophobicityo Isolated proteins are characterized by on-line electrospray ionization (ESI) time-of-flight mass spectrometry, by N-terminal sequencing, peptide mapping and characterization of posttranslational modifications.
In Specific Aim 2 genetic studies are performed on kindreds having AI or DGI, using a candidate gene approach. The five candidate genes for autosomal AI (enamelin & ameloblastin on 4ql 1-q21, MMP-20 on 1lq22, tuftelin on lq21-31, and kallikrein-4 on 19ql 3.3-ql 3.4), the one candidate gene for X-linked AI (amelogenin on Xp22.3-p22.1), the two candidate genes for DGI (DSPP and DMP1 on 4q21), and candidate genes identified discovered in the Proteomics study will be tested for linkage to dental disease. This study will provide gene-based diagnostic criteria, improved genetic counseling, and lead to the development of novel prevention and therapeutic strategies for families suffering from inherited disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE015846-04
Application #
7214881
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Scholnick, Steven
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$310,091
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Smith, Charles E; Hu, Yuanyuan; Hu, Jan C-C et al. (2018) Quantitative analysis of the core 2D arrangement and distribution of enamel rods in cross-sections of mandibular mouse incisors. J Anat :
Kim, Youn Jung; Seymen, Figen; Kang, Jenny et al. (2018) Candidate gene sequencing reveals mutations causing hypoplastic amelogenesis imperfecta. Clin Oral Investig :
Koruyucu, M; Kang, J; Kim, Y J et al. (2018) Hypoplastic AI with Highly Variable Expressivity Caused by ENAM Mutations. J Dent Res 97:1064-1069
Kim, Youn Jung; Kang, Jenny; Seymen, Figen et al. (2017) Analyses of MMP20 Missense Mutations in Two Families with Hypomaturation Amelogenesis Imperfecta. Front Physiol 8:229
Pham, Cong-Dat; Smith, Charles E; Hu, Yuanyuan et al. (2017) Endocytosis and Enamel Formation. Front Physiol 8:529
Klein, Ophir D; Duverger, Olivier; Shaw, Wendy et al. (2017) Meeting report: a hard look at the state of enamel research. Int J Oral Sci 9:e3
Wang, Shih-Kai; Hu, Yuanyuan; Yang, Jie et al. (2016) Fam83h null mice support a neomorphic mechanism for human ADHCAI. Mol Genet Genomic Med 4:46-67
Seymen, Figen; Kim, Youn Jung; Lee, Ye Ji et al. (2016) Recessive Mutations in ACPT, Encoding Testicular Acid Phosphatase, Cause Hypoplastic Amelogenesis Imperfecta. Am J Hum Genet 99:1199-1205
Yang, Jie; Kawasaki, Kazuhiko; Lee, Moses et al. (2016) The dentin phosphoprotein repeat region and inherited defects of dentin. Mol Genet Genomic Med 4:28-38
Parry, David A; Smith, Claire E L; El-Sayed, Walid et al. (2016) Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta. Am J Hum Genet 99:984-990

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