Gene therapy approaches involving constitutive overexpression of cDNAs encoding individual BMPs can induce bone formation and partially repair cranial and long bone defects as shown by this laboratory. However, this strategy is limited by the availability of BMP-responsive osteoprogenitor/stem cells at the regeneration site and lack of control over the timing and duration of regenerative factor expression. The underlying hypothesis of this competitive renewal is that bone regeneration can be greatly improved if gene therapy is used to mimic the natural processes of bone development and fracture repair characterized by the participation of multiple growth/differentiation factors whose expression is under tight temporal control. Of particular importance are factors such as BMPs that may function as heterodimers to stimulate progenitor differentiation and FGF2 that controls progenitor proliferation. This project, which contains both translational and basic science components, will compare the efficacy of regenerative approaches in well-defined preclinical models as well as explore underlying mechanisms by achieving the following specific aims:
Aim 1. Evaluate actions of an adenovirus expressing FGF2 (AdFGF2) on osteoprogenitor cell proliferation and differentiation in vitro and in vivo with or without Ad BMPs. Hypothesis: AdFGF2 can expand the population of osteogenic precursors at regeneration sites to enhance bone formation.
Aim 2. Use inducible gene expression systems to control the timing, duration and sequence of osteogenic factor synthesis. Hypothesis: Enhanced control of osteogenesis can be achieved using regulated gene expression to control the timing, duration and sequence of proliferative versus osteoqenic signals. This project will test novel regenerative concepts involving cooperative interactions between proliferative and osteogenic factors and temporal regulation of factor synthesis using simple rodent models. Approaches developed will provide proof of principle of the eventual development of new therapies for bone regeneration that mimic natural biological processes by providing temporal control over regenerative events.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013386-09
Application #
7782725
Study Section
Special Emphasis Panel (ZRG1-MOSS-B (02))
Program Officer
Lumelsky, Nadya L
Project Start
2000-03-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
9
Fiscal Year
2010
Total Cost
$322,198
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
Wilson, Christopher G; Martín-Saavedra, Francisco M; Padilla, Frédéric et al. (2014) Patterning expression of regenerative growth factors using high intensity focused ultrasound. Tissue Eng Part C Methods 20:769-79
Martin-Saavedra, Francisco M; Cebrian, Virginia; Gomez, Leyre et al. (2014) Temporal and spatial patterning of transgene expression by near-infrared irradiation. Biomaterials 35:8134-8143
Fabiilli, Mario L; Wilson, Christopher G; Padilla, Frédéric et al. (2013) Acoustic droplet-hydrogel composites for spatial and temporal control of growth factor delivery and scaffold stiffness. Acta Biomater 9:7399-409
Wilson, C G; Martin-Saavedra, F M; Vilaboa, N et al. (2013) Advanced BMP gene therapies for temporal and spatial control of bone regeneration. J Dent Res 92:409-17
Martín-Saavedra, Francisco M; Wilson, Christopher G; Voellmy, Richard et al. (2013) Spatiotemporal control of vascular endothelial growth factor expression using a heat-shock-activated, rapamycin-dependent gene switch. Hum Gene Ther Methods 24:160-70
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
Kwon, Tae-Geon; Zhao, Xiang; Yang, Qian et al. (2011) Physical and functional interactions between Runx2 and HIF-1? induce vascular endothelial growth factor gene expression. J Cell Biochem 112:3582-93
Zhang, Ying; Deng, Xiaopei; Scheller, Erica L et al. (2010) The effects of Runx2 immobilization on poly (epsilon-caprolactone) on osteoblast differentiation of bone marrow stromal cells in vitro. Biomaterials 31:3231-6
Jeong, Byung-Chul; Lee, Yong-Soo; Park, Yun-Yong et al. (2009) The orphan nuclear receptor estrogen receptor-related receptor gamma negatively regulates BMP2-induced osteoblast differentiation and bone formation. J Biol Chem 284:14211-8

Showing the most recent 10 out of 27 publications