The proper mineralization of bones and teeth has great importance in normal human growth and development including musculo-skeletal functions. The mineral phase in these tissues contributes to the hardness and comprehensive strength of the structure and also has a major physiological role as the metabolic reservoir of calcium and magnesium. Problems in the mineralization process are evident in a number of skeletal pathologies. One of the most interesting questions in mineralized tissue research is how, within the physiological environments, circulating calcium and phosphate and other mineral phase ions can be concentrated in specific, localized organs or tissues. Up until this point we have defined little about the process by which this cascade is initiated and regulated. However, the organic matrix has been implicated to have a major role in regulating the mineralization process. We have focussed our efforts primarily on dentin mineralization because it is a simpler system than bone, but the two mechanisms are probably closely related. Our basic hypothesis for matrix-mediated mineralization, is that acidic macromolecules first bind within the collagen matrix and these are responsible for nucleating and starting the mineralization cascade. Probably these acidic macromolecules also regulate the size of carbonated hydroxyapatite crystals. In the search for the gene encoding for the principle acidic noncollagenous protein (NCP) of dentin, namely phosphophoryn (PP) we identified 2 clones one representing phosphophoryn now named DMP2 (dentin matrix protein 2) and the other DMP3 (dentin matrix protein 3) which is a compound of dentin sialoprotein and a mini """"""""phosphophoryn""""""""like domain. The amino acid sequence deduced from the partial DMP2 cDNA is of special interest because it clearly represents an aspartic acid and serine rich acidic protein of the type to be expected of a dentin matrix component. This gene has been tightly localized to mouse chromosome 5q21, equivalent to human chromosome 4Q21. This chromosome location is especially interesting because of the linkage of human chromosome 4q13-21 with the dentin mineralization disorder dentinogenesis imperfecta type II. In order to expand our understanding of the DMP2 gene structure and its function we propose the following specific aims: (1) To determine the complete primary structure of rat DMP2 (2) To delineate DMP2 promoter sequences and identify elements involved in tissue -specific regulation (3) To clone the human DMP2 gene in order to ultimately identify gene alterations in patients with Dentinogenesis Imperfecta Type II (4) To examine the temporal and spatial patterns of DMP2 expression during tooth development (5) To determine the calcium binding property of DMP2. The long-term goal is to understand the regulatory mechanism of DMP2 in dentin mineralization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE013836-01A2
Application #
6433916
Study Section
Special Emphasis Panel (ZRG1-GRM (03))
Program Officer
Lumelsky, Nadya L
Project Start
2002-01-01
Project End
2006-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
1
Fiscal Year
2002
Total Cost
$267,001
Indirect Cost
Name
University of Illinois at Chicago
Department
Dentistry
Type
Schools of Dentistry
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Hao, Jianjun; Ramachandran, Amsaveni; George, Anne (2009) Temporal and spatial localization of the dentin matrix proteins during dentin biomineralization. J Histochem Cytochem 57:227-37
Chaussain, Catherine; Eapen, Asha Sarah; Huet, Eric et al. (2009) MMP2-cleavage of DMP1 generates a bioactive peptide promoting differentiation of dental pulp stem/progenitor cell. Eur Cell Mater 18:84-95
George, Anne; Veis, Arthur (2008) Phosphorylated proteins and control over apatite nucleation, crystal growth, and inhibition. Chem Rev 108:4670-93
Hao, Jianjun; Narayanan, Karthikeyan; Muni, Tanvi et al. (2007) Dentin matrix protein 4, a novel secretory calcium-binding protein that modulates odontoblast differentiation. J Biol Chem 282:15357-65
Narayanan, Karthikeyan; Gajjeraman, Sivakumar; Ramachandran, Amsaveni et al. (2006) Dentin matrix protein 1 regulates dentin sialophosphoprotein gene transcription during early odontoblast differentiation. J Biol Chem 281:19064-71
He, Gen; Ramachandran, Amsaveni; Dahl, Tom et al. (2005) Phosphorylation of phosphophoryn is crucial for its function as a mediator of biomineralization. J Biol Chem 280:33109-14
Hao, Jianjun; He, Gen; Narayanan, Karthikeyan et al. (2005) Identification of differentially expressed cDNA transcripts from a rat odontoblast cell line. Bone 37:578-88
George, Anne; Hao, Jianjun (2005) Role of phosphophoryn in dentin mineralization. Cells Tissues Organs 181:232-40
Narayanan, Karthikeyan; Ramachandran, Amsaveni; Peterson, Mathew Craig et al. (2004) The CCAAT enhancer-binding protein (C/EBP)beta and Nrf1 interact to regulate dentin sialophosphoprotein (DSPP) gene expression during odontoblast differentiation. J Biol Chem 279:45423-32
Hao, Jianjun; Zou, Bingshuang; Narayanan, Karthikeyan et al. (2004) Differential expression patterns of the dentin matrix proteins during mineralized tissue formation. Bone 34:921-32

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