Glucose regulated protein-78 (GRP78) is a dynamic endoplasmic reticulum chaperone of the heat shock family that is involved in the unfolded protein and cellular stress response. GRP78 and other GRPs are known to bind Ca2+ in the ER to modulate the levels of calcium in the cell and respond to ER stress. We have demonstrated earlier that GRP78 is expressed by osteoblasts and odontoblasts and localized in the mineralized matrices of bone and dentin. Interestingly, GRP78 functions as a receptor for dentin matrix protein 1 (DMP1), a key protein involved in matrix mineralization. In this proposal, we will explore the synergistic function of GRP78 and DMP1 during mineralization. Previous studies demonstrate that upon stress, GRP78 can translocate from the ER to the cell surface. Additionally, our lab showed that GRP78 is a receptor for DMP1.
We aim to understand how GRP78 interacts with DMP1 to promote osteogenic differentiation and matrix mineralization in periodontal ligament stem cells; moreover, we will determine the mechanism of GRP78-DMP1 complex internalization and subsequent translocation intracellularly to aid in cell differentiation through in vitro cell culture work. Through an in vivo mouse model, we will determine the functional significance of GRP78 in mineralization with periodontal ligament stem cells. Overall, our overarching goal will be to determine GRP78?s functional significance in mineralization to ultimately provide a novel way to achieve bone regeneration in the periodontium.

Public Health Relevance

This study aims to understand the interaction of Dentin Matrix Protein-1 (DMP1) and Glucose Regulated Protein-78 (GRP78) and how they function in the differentiation periodontal ligament stem cells and in mineralization. We will gain insight into how ER stress influences the interactions of DMP1 and GRP78 on PDLSCs and how it alters their biochemistry, architecture, and molecular interactions. This knowledge will give us a deeper understanding of biomineralization and lead to more reliable and effect ways of tissue regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30DE027601-01A1
Application #
9610069
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Frieden, Leslie A
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Dentistry/Oral Hygn
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612