The long-term goal of this project is to understand the molecular mechanisms that control biomineralization. We originally identified Dentin matrix protein 1 (DMP1) a noncollagenous protein in odontoblasts and later in osteoblasts. Numerous studies by us and others suggest that DMP1 might play critical roles in the biomineralization process. Recently we discovered that DMP1 can stimulate the release of intracellular calcium in preosteoblasts and preodontoblasts. To refill the ER, plasma membrane Ca 2+ channels need to be activated to permit Ca 2+ entry from the extracellular space. The molecular mechanism by which DMP1 stimulation leads to store depletion and subsequent opening of Ca2+ permeable ion channels namely store-operated calcium channels are not known. Therefore, understanding how DMP1 mediates intracellular calcium release and influx is a new concept. Store operated calcium entry (SOCE) is a principal cellular process by which cells regulate basal Ca2+, refill intracellular Ca2+ and execute a wide range of specialized activities. We also identified two DMP1 interacting proteins, namely, GRP-78 (Glucose-regulated protein- 78) and TRIP-1 (TGF-beta receptor II interacting protein 1). Both GRP-78 and TRIP-1 are ER resident proteins. Thus, the epicenter for DMP1 stimulation is the endoplasmic reticulum. The unifying hypothesis of this proposal is that the release of intracellular Ca2+ by DMP1 stimulation regulates a wide range of cellular functions including osteoblast and odontoblast survival and differentiation. The result wil generate new information that is relevant to understanding molecular mechanisms that control mineralization in bone and dentin. Currently, no channel molecule has been exploited for either therapy or diagnosis of mineralization related disorders. Therefore, the outcomes from this study will help define potential therapeutic targets for bone and dentin repair and regeneration.

Public Health Relevance

Mineralization is a ubiquitous process and is fundamental to human development and health. Dysfunctional mineralization leads to a variety of medical problems and so an understanding of these processes is essential. The proposed studies are designed to understand the function of dentin matrix protein 1 (DMP1) in the biomineralization process. The mechanisms by which DMP1 functions in bone and teeth are poorly understood. The proposed experiments are designed to fill this gap. We identified that DMP1 can cause the release of calcium from intracellular stores. However, the mechanism by which DMP1 stimulation leads to store depletion and subsequent opening of Ca2+ permeable channels are not known. Store operated calcium entry is a key mechanism by which cells convey Ca2+ signals and maintain Ca2+ homeostasis. Dysregulated calcium entry is detrimental to osteoblasts and odontoblasts. We also identified novel DMP1 partners that can perform various functions in matrix mineralization Understanding the mechanism by which intracellular Ca2+ is regulated and identifying the function of DMP1 partners will have important implications in developing novel strategies for bone and dentin repair and regeneration.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DE011657-16A1
Application #
8743403
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wan, Jason
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
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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