Dentinogenesis is a dynamic process that involves a cascade of cellular and extracellular events. Specific interactive events like cell-cell, cell-matrix and matrix-matrix are responsible for odontoblast differentiation and the assembly of the mineralized dentin matrix. Problems in the mineralization process are evident in a number of dental pathologies. Successful dentin regeneration and repair in dentistry relies on the ability to recruit odontoblast precursors to the site followed by maturation process of these cells, matrix deposition and ultimately mineralization of the organic matrix. Noncollagenous acidic proteins have been postulated to play a regulatory role in de novo mineral nucleation, regulating hydroxyapatite crystal size as well as its morphology. Dentin matrix protein 1 (DMP1) is an extracellular matrix protein that was first cloned by us from an odontoblast cDNA library. DMP1 is typically anionic and has multiple calcium binding sites and is thought to promote mineralization by nucleating hydroxyapatite. An intriguing finding that we have reported is that DMP1 can perform multiple functions. Non-phosphorylated DMP1 was found to translocate to the nucleus during early differentiation of odontoblasts and function in regulating the expression of biomineralization-specific genes. The central hypothesis of the proposed studies is that DMP1 plays an important and unique role during maturation of odontoblasts, leading to the formation of mineralized dentin. Therefore 3 specific aims are proposed to pursue the mechanisms responsible for DMP1 mediated odontoblast differentiation and mineralized matrix formation: (1) To study the cellular targets of DMP1 during odontoblast differentiation;(2) To elucidate the molecular mechanisms of DMP1 gene regulation during odontoblast differentiation;(3) To determine if DMP1 can induce odontoblast lineage in stem cells. Understanding the mineralization process is important to the biomedical and dentistry fields as disruption of normal biomineralization can lead to pathological calcification or demineralization process. The long-term goal is to understand the regulatory mechanism by which DMP1 plays a unique role in dentin mineralization.

Public Health Relevance

Odontoblasts, the principal cells responsible for dentin formation synthesize proteins that are responsible for dentin mineralization. One such protein that we have identified is Dentin matrix protein 1. In this proposal we intend to identify the mechanism by which this molecule functions in the odontoblast differentiation process. Once we have characterized the function of DMP1 in dentin formation, then we could use this molecule for regenerating dentin and thus replace synthetic materials that are currently being used in endodontic practise.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011657-15
Application #
8270339
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (09))
Program Officer
Lumelsky, Nadya L
Project Start
1996-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
15
Fiscal Year
2012
Total Cost
$373,148
Indirect Cost
$135,474
Name
University of Illinois at Chicago
Department
Dentistry
Type
Schools of Dentistry
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Ramachandran, Amsaveni; Ravindran, Sriram; Huang, Chun-Chieh et al. (2016) TGF beta receptor II interacting protein-1, an intracellular protein has an extracellular role as a modulator of matrix mineralization. Sci Rep 6:37885
Padovano, J D; Ravindran, S; Snee, P T et al. (2015) DMP1-derived peptides promote remineralization of human dentin. J Dent Res 94:608-14
Ravindran, Sriram; George, Anne (2015) Dentin Matrix Proteins in Bone Tissue Engineering. Adv Exp Med Biol 881:129-42
Ravindran, Sriram; Kotecha, Mrignayani; Huang, Chun-Chieh et al. (2015) Biological and MRI characterization of biomimetic ECM scaffolds for cartilage tissue regeneration. Biomaterials 71:58-70
Pothirajan, Padmabharathi; Ravindran, Sriram; George, Anne et al. (2014) Magnetic resonance spectroscopy and imaging can differentiate between engineered bone and engineered cartilage. Conf Proc IEEE Eng Med Biol Soc 2014:3929-32
Huang, Chun-Chieh; Ravindran, Sriram; Yin, Ziying et al. (2014) 3-D self-assembling leucine zipper hydrogel with tunable properties for tissue engineering. Biomaterials 35:5316-26
Muni, Tanvi; Mrksich, Milan; George, Anne (2014) Self-assembled monolayer facilitates epithelial-mesenchymal interactions mimicking odontogenesis. Connect Tissue Res 55:26-33
Jacob, Alexander; Zhang, Youbin; George, Anne (2014) Transcriptional regulation of dentin matrix protein 1 (DMP1) in odontoblasts and osteoblasts. Connect Tissue Res 55 Suppl 1:107-12
Ravindran, Sriram; George, Anne (2014) Multifunctional ECM proteins in bone and teeth. Exp Cell Res 325:148-54
Padovano, Joshua D; Ramachandran, Amsaveni; Bahmanyar, Sara et al. (2014) Bone-specific overexpression of DMP1 influences osteogenic gene expression during endochondral and intramembranous ossification. Connect Tissue Res 55 Suppl 1:121-4

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