Dr. Franceschi and his colleagues propose to study the molecular mechanisms by which ascorbic acid regulates the differentiation program in osteoblasts. They plan to continue their investigations of the regulation of levels of ascorbic acid in osteoblasts both by studying the AA transport pathway as well as the enzyme responsible for the reduction of dehydroascorbic acid to the active form, ascorbate. They will then determine the effects of specific hormones and drugs on the activities of these two independent determinants of intracellular levels of ascorbate. A second major aim of this proposal focuses on understanding the mechanism by which ascorbate impacts on the transcription of genes encoding bone-specific proteins. Dr. Franceschi and his colleagues have recently shown that the ascorbate effect is likely mediated through secretion of matrix collagen. Their investigation of transcription factors will focus predominantly on basic helix/loop/helix proteins and their interaction with Id proteins. These experiments are predicated on recent observations that a splice variant of Id-1 is down-regulated when osteoblasts are treated with ascorbic acid. Investigators will then use the osteocalcin gene as a model for investigating cis elements that are necessary for induction by ascorbic acid. They plan transfection experiments in which portions of the osteocalcin 5' flank will be attached to a reporter gene in order to define which elements are necessary and sufficient for the ascorbic acid induction. These functional experiments will be supplemented with gel shift and footprinting studies in order to more precisely define functionally important cis elements that bind candidate transcription factors. There will be particular interest in E box sequences that would be putative elements for repression by the Id family of proteins. These studies will enable Dr. Franceschi and his colleagues to gain a better understanding of the mechanisms by which ascorbate affects the programming of bone cell differentiation at the molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011723-05
Application #
2897095
Study Section
Special Emphasis Panel (ZRG4-NTN (06))
Program Officer
Mcgowan, Joan A
Project Start
1995-09-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2001-06-30
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Franceschi, Renny T; Ge, Chunxi (2017) Control of the Osteoblast Lineage by Mitogen-Activated Protein Kinase Signaling. Curr Mol Biol Rep 3:122-132
Ge, Chunxi; Wang, Zhengyan; Zhao, Guisheng et al. (2016) Discoidin Receptor 2 Controls Bone Formation and Marrow Adipogenesis. J Bone Miner Res 31:2193-2203
Ge, C; Zhao, G; Li, Y et al. (2016) Role of Runx2 phosphorylation in prostate cancer and association with metastatic disease. Oncogene 35:366-76
Lee, Eunsohl; Wang, Jingcheng; Yumoto, Kenji et al. (2016) DNMT1 Regulates Epithelial-Mesenchymal Transition and Cancer Stem Cells, Which Promotes Prostate Cancer Metastasis. Neoplasia 18:553-66
Stechschulte, Lance A; Ge, Chunxi; Hinds Jr, Terry D et al. (2016) Protein Phosphatase PP5 Controls Bone Mass and the Negative Effects of Rosiglitazone on Bone through Reciprocal Regulation of PPAR? (Peroxisome Proliferator-activated Receptor ?) and RUNX2 (Runt-related Transcription Factor 2). J Biol Chem 291:24475-24486
Ge, Chunxi; Cawthorn, William P; Li, Yan et al. (2016) Reciprocal Control of Osteogenic and Adipogenic Differentiation by ERK/MAP Kinase Phosphorylation of Runx2 and PPAR? Transcription Factors. J Cell Physiol 231:587-96
Park, Y; Hosomichi, J; Ge, C et al. (2015) Immortalization and characterization of mouse temporomandibular joint disc cell clones with capacity for multi-lineage differentiation. Osteoarthritis Cartilage 23:1532-42
McElderry, John-David P; Zhao, Guisheng; Khmaladze, Alexander et al. (2013) Tracking circadian rhythms of bone mineral deposition in murine calvarial organ cultures. J Bone Miner Res 28:1846-54
Danciu, Theodora E; Li, Yan; Koh, Amy et al. (2012) The basic helix loop helix transcription factor Twist1 is a novel regulator of ATF4 in osteoblasts. J Cell Biochem 113:70-9
Wang, Weizhuo; Olson, Douglas; Liang, Gang et al. (2012) Collagen XXIV (Col24?1) promotes osteoblastic differentiation and mineralization through TGF-?/Smads signaling pathway. Int J Biol Sci 8:1310-22

Showing the most recent 10 out of 36 publications