A proposal is presented for the formal training of a veterinary surgeon in the molecular and genetic aspects of cartilage repair. The candidate is board certified with the American College of Veterinary Medicine, and possesses a Master of Science in Pharmacology and a PhD in Cellular and Molecular Biology. The training proposed in the grant would prepare the candidate for a career as an independent, nationally competitive research scientist. There are two phases in which the training is divided. Phase I will consist of intense training in the development of a gene therapeutic vector and microarray and proteomic analysis as they relate to cartilage repair. As the candidate masters various scientific and laboratory skills in vector development, genomics and proteomics, she will transition to Phase II and carry out the animal studies in a more independent manner while having her mentors available to consult on study design, execution and analysis. Arthritis is the most prevalent disease affecting humans. Despite extensive drug therapy, there is no cure. Growth factors are known to have important biologic effects in intrinsic repair.
The aim of the proposed research is to develop a gene therapy protocol for the sustained local release of Insulin-Like Growth Factor-l (IGF-I) in amounts sufficient to promote healing of equine articular cartilage. IGF-I has an important role in cartilage development and homeostasis, and in previous studies has been shown to promote healing in experimentally injured cartilage. An important limitation however has been the inability to sustain therapeutic levels of IGF-I at the site of injury. To overcome this limitation, it is proposed to use an adenoassociated or lentiviral vector to introduce an IGF-I gene construct into equine chondrocytes and synoviocytes. After extensive testing in vitro, genetically modified chondrocytes would be imported into experimentally injured joints, with the resulting repair tissue examined at predetermined intervals. The outlined plan of training and the resources available provide the candidate with an outstanding opportunity to develop expertise and scientific independence in gene therapy approaches to cartilage disease. Lay:Despite extensive drug therapy for arthritis there is no cure. Gene therapy involves the transfer of therapeutic genes (DMA) to improve cartilage repair. This proposal involves the development of Insulin-Like Growth Factor-l gene therapy to improve cartilage health and reduce the incidence of osteoarthritis following cartilage injury.
|Hemphill, Daniel D; McIlwraith, C Wayne; Samulski, R Jude et al. (2014) Adeno-associated viral vectors show serotype specific transduction of equine joint tissue explants and cultured monolayers. Sci Rep 4:5861|
|Carpenter, Ryan S; Goodrich, Laurie R; Frisbie, David D et al. (2010) Osteoblastic differentiation of human and equine adult bone marrow-derived mesenchymal stem cells when BMP-2 or BMP-7 homodimer genetic modification is compared to BMP-2/7 heterodimer genetic modification in the presence and absence of dexamethasone. J Orthop Res 28:1330-7|
|Goodrich, L R; Choi, V W; Carbone, B A Duda et al. (2009) Ex vivo serotype-specific transduction of equine joint tissue by self-complementary adeno-associated viral vectors. Hum Gene Ther 20:1697-702|