Gene therapeutic approaches to cartilage repair

软骨修复的基因治疗方法

• 批准号: 8088068
• 负责人: Laurie Goodrich
• 金额: $ 12.24万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088068
• 关键词: Adenoviruses; Adult; Affect; American; Animals; Arthritis; Biochemical; Biomechanics; Cartilage; Cartilage Diseases; Cartilage Matrix; Cartilage injury; Cell Proliferation; Cell Survival; Cells; Characteristics; Chondrocytes; Chronic; Code; Collaborations; Collagen; Collagen Type I; Collagen Type II; Consult; Cytomegalovirus; Defect; Degenerative polyarthritis; Dependovirus; Development; Disease; Doctor of Philosophy; Dose; Equus caballus; Extracellular Matrix; Gene Expression; Genes; Genetic; Genomics; Grant; Green Fluorescent Proteins; Growth Factor; Growth Factor Gene; Half-Life; Healed; Health; Homeostasis; Human; Hyaluronan; In Vitro; Incidence; Inferior; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor I; Intra-Articular Injections; Joint Capsule; Joints; Laboratories; Length; Lentivirus Vector; Life; Master of Science; Measures; Mentors; Messenger RNA; Metabolism; Modification; Molecular; Molecular Genetics; Molecular Profiling; Molecular and Cellular Biology; Morphology; North Carolina; Osteoarthrosis Deformans; Outcome; Pain; Pharmacology; Pharmacotherapy; Phase; Production; Proteins; Proteoglycan; Proteomics; Protocols documentation; Recombinant Insulin-Like Growth Factor; Research; Research Design; Resources; Role; Running; Scientist; Serotyping; Site; Somatomedins; Subfamily lentivirinae; Surgeon; Testing; Therapeutic; Thick; Time; Tissues; Training; Transgenes; Transplantation; Universities; Up-Regulation; Vertebral column; Veterinary Medicine; Viral; Viral Vector; Wound Healing; aggrecan; arthropathies; articular cartilage; career; cartilage cell; cartilage development; cartilage repair; cell type; college; cytokine; extracellular; gene therapy; healing; immunogenicity; implantation; improved; in vitro testing; in vivo; injured; novel; osteochondral tissue; promoter; protein expression; repaired; skills; therapeutic gene; transduction efficiency; vector

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.

描述(由申请人提供)：建议对一名兽医进行软骨修复的分子和遗传学方面的正式培训。应聘者拥有美国兽医学院的董事会认证，并拥有药理学硕士学位和细胞和分子生物学博士学位。拨款中提议的培训将为候选人成为一名独立的、在全国具有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和微阵列的密集培训，以及与软骨修复相关的蛋白质组分析。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，以更独立的方式进行动物研究，同时让她的导师为研究设计、执行和分析提供咨询。关节炎是影响人类的最常见疾病。尽管进行了广泛的药物治疗，但没有治愈的方法。生长因子在内源性修复中具有重要的生物学效应。这项研究的目的是开发一种局部持续释放胰岛素样生长因子-L(IGFI)的基因治疗方案，其量足以促进马关节软骨的愈合。IGF-I在软骨发育和动态平衡中起着重要的作用，先前的研究表明IGF-I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-I。为了克服这一局限性，有人建议使用腺相关或慢病毒载体将IGF-I基因结构导入马的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输入到实验损伤的关节中，并以预定的间隔检查产生的修复组织。概述的培训计划和可用的资源为候选人提供了一个发展软骨疾病基因治疗方法方面的专业知识和科学独立性的绝佳机会。莱伊：尽管对关节炎进行了广泛的药物治疗，但仍然没有治愈的方法。基因治疗涉及治疗基因(DMA)的转移，以改善软骨修复。这项建议涉及开发胰岛素样生长因子-L基因疗法，以改善软骨健康，减少软骨损伤后骨关节炎的发生率。