Gene therapeutic approaches to cartilage repair

描述（由申请人提供）：提出了一项关于软骨修复分子和遗传方面的兽医正式培训的建议。候选人获得美国兽医学院董事会认证，拥有药理学硕士学位和细胞与分子生物学博士学位。资助中提出的培训将为候选人成为一名独立的、具有全国竞争力的研究科学家做好准备。培训分为两个阶段。第一阶段将包括开发基因治疗载体、微阵列和蛋白质组学分析，因为它们与软骨修复有关。由于候选人掌握了载体开发、基因组学和蛋白质组学方面的各种科学和实验室技能，她将过渡到第二阶段，以更独立的方式开展动物研究，同时有导师在研究设计、执行和分析方面提供咨询。关节炎是影响人类最普遍的疾病。尽管进行了广泛的药物治疗，但仍无法治愈。已知生长因子在内在修复中具有重要的生物学作用。拟议研究的目的是开发一种基因治疗方案，用于持续局部释放足以促进马关节软骨愈合的胰岛素样生长因子- 1 （IGF-I）。igf - 1在软骨发育和体内平衡中起着重要作用，在先前的研究中已被证明可以促进实验性损伤软骨的愈合。然而，一个重要的限制是无法在损伤部位维持治疗水平的igf - 1。为了克服这一限制，建议使用腺相关或慢病毒载体将igf - 1基因构建物引入马软骨细胞和滑膜细胞。经过广泛的体外测试，基因修饰的软骨细胞将被导入实验损伤的关节，并在预定的时间间隔检查修复组织。概述的培训计划和现有资源为候选人提供了一个在软骨疾病基因治疗方法方面发展专业知识和科学独立性的绝佳机会。雷：尽管对关节炎进行了广泛的药物治疗，但仍无法治愈。基因治疗涉及治疗基因（DMA）的转移，以改善软骨修复。这一建议涉及胰岛素样生长因子- 1基因治疗的发展，以改善软骨健康和减少软骨损伤后骨关节炎的发生率。

DESCRIPTION (provided by applicant): 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.