This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Tendon injuries affect more than 400,000 people annually in US alone. The tendon injuries are a frustrating and devastating problem in the clinic and are critical for functional return after severe trauma, amputations, and rheumatoid arthritis. It is responsible for loss of more than 5 million workdays, and an overall economic impact of $15 billion annually. Repair ruptures or adhesion formations have been well-known problems associated with repairs of intrasynovial flexor tendons. Strengthening the repairs, decreasing rupture rate, and limiting adhesions have been a major focus of clinical and research efforts. Our preliminary studies showed that transfer of basic fibroblast growth factor (bFGF) gene through adeno-associated viral (AAV2) vectors significantly increased the strength of healing tendons 4 weeks after repairs and that AAV2-bFGF gene therapy promoted collagen synthesis. These evidences coupled with our findings that AAV2 vector elicited far less tissue reactions than adenoviral vectors and liposomes lead us to postulate that transfer of exogenous bFGF gene through AAV2 vector would drastically accelerate tendon healing process and hold a great promise to enhance strength of the lacerated intrasynovial tendons. This proposed study, based on our previous in vitro and in vivo studies, aims to optimize the dosage of AAV2-bFGF thus maximizing the effects, to investigate effects of AAV2-bFGF gene therapy over an extended period of tendon healing, and to carry out clinical trials of the gene therapy for injured digital flexor tendons.
Our specific aims will be (1) to determine the optimal doses of AAV2-bFGF injection into the tendon, (2) to investigate the changes in the strength and adhesions of the tendon at varying intervals over a critical period of time in a clinical relevant rabbit tendon laceration model, (3) to investigate persistence of transgene expression and immune responses, and (4) to produce AAV2-hbFGF and to perform clinical trials to test safety and efficiency of the proposed gene therapy for tendon repairs. Gene expression of and production of growth factors and matrix components in the tendon, biomechanics and morphology of the tendons will be included in evaluation of biological effects of this approach in animal studies. The ultimate goal of our work is to develop a novel molecular approach to treat the problem of repair ruptures and adhesion formation of the injured intrasynovial tendons which are inherently of low growth factor activities and lack adequate healing potential.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
2P20RR018757-06
Application #
7725261
Study Section
Special Emphasis Panel (ZRR1-RI-6 (01))
Project Start
2008-06-05
Project End
2009-04-30
Budget Start
2008-06-05
Budget End
2009-04-30
Support Year
6
Fiscal Year
2008
Total Cost
$39,223
Indirect Cost
Name
Roger Williams Hospital
Department
Type
DUNS #
625899281
City
Providence
State
RI
Country
United States
Zip Code
02908
Kim, Joseph W; Vang, Souriya; Luo, John Zq et al. (2017) Effects of bone marrow on the microenvironment of the human pancreatic islet: A Protein Profile Approach. Mol Cell Endocrinol 450:32-42
Luo, John Z Q; Kim, Joseph W; Luo, LuGuang (2016) EFFECTS OF GINSENG AND ITS FOUR PURIFED GINSENOSIDES (Rb2, Re, Rg1, Rd) ON HUMAN PANCREATIC ISLET ? CELL IN VITRO. Eur J Pharm Med Res 3:110-119
Tang, Jin Bo; Wu, Ya Fang; Cao, Yi et al. (2016) Basic FGF or VEGF gene therapy corrects insufficiency in the intrinsic healing capacity of tendons. Sci Rep 6:20643
Kim, Joseph W; Luo, John Z; Luo, Luguang (2015) The Biochemical Cascades of the Human Pancreatic ?-Cells: The Role of MicroRNAs. J Bioanal Biomed 7:
Luo, Lu Guang; Xiong, Fang; Ravassard, Philippe et al. (2015) Human Bone Marrow Subpopulations Sustain Human Islet Function and Viability In vitro. Br J Med Med Res 8:576-587
Ilgun, Handenur; Kim, Joseph William; Luo, LuGuang (2015) Adult Stem Cells and Diabetes Therapy. J Stem Cell Res Transplant 2:
Bartos, Adrian; Dubielecka, Patrycja M (2014) The emerging role of Bcr-Abl-induced cystoskeletal remodeling in systemic persistence of leukemic stem cells. Curr Drug Deliv 11:582-91
Chorzalska, A; Dubielecka, P M (2014) New Abelson interactor-1 (Abi-1)-driven mechanism of acquired drug resistance. Leuk Suppl 3:S7-8
Chorzalska, A; Salloum, I; Shafqat, H et al. (2014) Low expression of Abelson interactor-1 is linked to acquired drug resistance in Bcr-Abl-induced leukemia. Leukemia 28:2165-77
Michalczyk, Izabela; Sikorski, Aleksander F; Kotula, Leszek et al. (2013) The emerging role of protein kinase C? in cytoskeletal signaling. J Leukoc Biol 93:319-27

Showing the most recent 10 out of 90 publications