Gene therapeutic approaches to cartilage repair

描述（由申请人提供）：提出了一项建议，对兽医进行软骨修复的分子和遗传方面的正式培训。该候选人获得了美国兽医学院的认证，并拥有药理学硕士学位和细胞与分子生物学博士学位。赠款中提议的培训将使候选人为成为一名独立的、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。第一阶段将包括在基因治疗载体和微阵列和蛋白质组学分析的发展，因为它们涉及到软骨修复的密集培训。随着候选人掌握载体开发，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，并以更独立的方式进行动物研究，同时让她的导师就研究设计，执行和分析进行咨询。关节炎是影响人类的最普遍的疾病。尽管进行了广泛的药物治疗，但仍无法治愈。已知生长因子在内源性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，用于持续局部释放胰岛素样生长因子-1（IGF-I），其量足以促进马关节软骨的愈合。IGF-I在软骨发育和体内平衡中具有重要作用，并且在先前的研究中已显示出促进实验性损伤软骨的愈合。然而，一个重要的限制是不能在损伤部位维持治疗水平的IGF-I。为了克服这一局限性，提出使用腺相关或慢病毒载体将IGF-1基因构建体引入马软骨细胞和滑膜细胞。经过广泛的体外测试后，转基因软骨细胞将被导入实验性损伤的关节，并在预定的时间间隔内检查由此产生的修复组织。概述的培训计划和可用的资源为候选人提供了一个出色的机会，以发展软骨疾病基因治疗方法的专业知识和科学独立性。躺：尽管广泛的药物治疗关节炎，但没有治愈。基因治疗涉及治疗基因（DMA）的转移，以改善软骨修复。该提案涉及开发胰岛素样生长因子-1基因疗法，以改善软骨健康并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.