The long term goal of this project is to develop gene therapy as a viable approach for the tissue engineering of bone at oral and extraoral sites. Bone loss due to periodontal disease, neoplasia, trauma or reconstructive surgery is a major worldwide problem. Because current or emerging regenerative treatments using either bone grafts or recombinant proteins all have severe limitations, there is a need for new regenerative approaches. Gene therapy represents an exciting new alternative for stimulating bone formation. Genes for bone morphogenetic proteins (BMPs) are introduced into the patient at the desired site for bone regeneration. Recipient cells are then converted into mini-reactors to produce sustained levels of regenerative molecules. Preliminary studies with an engineered adenovirus expressing BMP7 support the feasibility of this approach in that this virus can induce ectopic bone formation at both subcutaneous and intramuscular sites. Two hypotheses will be tested in this project: 1) Host cells transduced with adenovirus vectors encoding bone morphogenetic proteins will produce sustained levels of regenerative molecules capable of inducing substantial new bone formation at both ectopic and orthotopic sites, 2) The BMP-driven regenerative process will recapitulate central events occurring in embyonic bone development and can be manipulated by altering the expression of other developmentally regulated factors. These hypotheses will be addressed by achieving the following specific aims: 1) Construct human adenovirus vectors expressing BMPs and optimize matrix carriers and conditions for in vivo viral delivery to cells, 2) Compare the osteogenic activity of adenovirus expressing BMPS 3, 4, and 7 alone and in combination using an in vivo mouse skin pouch model, 3) Examine the activity of optimized viral vector/matrix combinations showing strong osteogenic activity in Aim 2 for ability to form bone in both cranial and long bone critical size defect models, 4) Define early events following BMP virus transduction and manipulate the BMP response with known upstream and downstream modulators of BMP action. These studies will greatly advance our understanding of BMP-dependent bone regeneration and develop a viable gene therapy approach for regenerating bone in the craniofacial and appendicular skeleton.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013386-03
Application #
6516575
Study Section
Special Emphasis Panel (ZDE1-YA (32))
Program Officer
Kousvelari, Eleni
Project Start
2000-03-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
3
Fiscal Year
2002
Total Cost
$230,844
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
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