Gene Transfer Treatment of Articular Cartilage Damage

描述（由申请人提供）：关节软骨损伤仍然是 骨科领域的未解决问题拟议研究的目的是 阐明自分泌/旁分泌机制在生长中的潜在作用 因子介导的关节软骨修复。这些研究将采用体外 重组腺相关病毒（rAAV）介导的基因转移方法， 检验以下假设：（1）本地生长因子生产可以 通过rAAV载体介导的基因转移至牛关节软骨细胞实现 并将在急性软骨创伤中增强软骨修复;（2）局部生长 因子生产可以通过rAAV载体介导的基因转移来实现， 人关节软骨细胞并将增强骨关节炎修复 软骨;（3）可以实现一种以上生长因子的局部产生 通过rAAV载体介导的基因转移和表达的生长因子将 在创伤和骨关节炎软骨修复的调节中相互作用 损伤;和（4）局部生长因子的产生，再加上 生长因子受体可以通过rAAV介导的基因转移来实现， 软骨细胞，并将增强创伤和OA软骨损伤的修复。 将使用胰岛素样生长因子I（IGF-I）和 成纤维细胞生长因子-2（FGF-2）和在目标4中的I型IGF受体 （IGF-IR）。将使用生物合成、组织学、生物化学 和生物力学参数。这些研究表明， 因子介导的软骨修复可以通过自分泌/旁分泌 机制不仅可以深入了解这些因素在 软骨调节，但可能有助于促进未来的发展， 潜在的基因转移疗法

DESCRIPTION (provided by applicant): Articular cartilage damage remains an unsolved problem in orthopaedics. The purpose of the proposed studies is to elucidate the potential role of autocrine/paracrine mechanisms in growth factor-mediated articular cartilage repair. The studies will employ in vitro recombinant adeno-associated virus (rAAV) mediated gene transfer methods to test the following hypotheses: (1) local growth factor production can be achieved by rAAV vector-mediated gene transfer to bovine articular chondrocytes and will augment cartilage repair in acute cartilage trauma; (2) local growth factor production can be achieved by rAAV vector-mediated gene transfer of human articular chondrocytes and will augment repair of osteoarthritic cartilage; (3) local production of more than one growth factor can be achieved by rAAV vector-mediated gene transfer and expressed growth factors will interact in the regulation of repair in traumatic and osteoarthritic cartilage damage; and (4) local growth factor production, coupled with expression of growth factor receptors can be achieved by rAAV-mediated gene transfer to chondrocytes and will augment repair in traumatic and OA cartilage damage. These hypotheses will be tested using insulin-like growth factor I (IGF-I) and fibroblast growth factor-2, (FGF-2) and, in Aim 4, the type I IGF receptor (IGF-IR). Repair will be assessed using biosynthetic, histological, biochemical and biomechanical parameters. The demonstration by these studies that growth factor-mediated cartilage repair can be achieved through autocrine/paracrine mechanisms would not only lend insight into the role of these factors in cartilage regulation, but may serve to facilitate the development of future potential gene transfer-based therapies.