Genetic Mouse Models of Cartilage Healing

描述（由申请人提供）：本提案来自骨科软骨生物学家琳达桑德尔博士和解剖学和神经生物学系群体遗传学家吉姆切弗鲁德博士。我们建议确定遗传定义的小鼠模型的软骨愈合。最近，关节软骨愈合和骨关节炎（OA）的保护之间的直接相关性已被证明。这将是一个大规模的项目，为研究有助于软骨愈合从而导致OA的基因创造了独特的资源。Cheverud博士目前使用“超级愈合”小鼠研究有助于身体大小的基因，并开发了12种含有部分基因组的近交系小鼠，以及40代大（愈合）和小（非愈合）小鼠之间的高级杂交。已经证明，亲本“超级愈合”小鼠能够比对照小鼠显著更好地再生软骨。在骨科，我们已经建立了骨折愈合，软骨愈合和韧带愈合的小鼠模型，并将在实验动物中进行全层软骨伤口。解剖学和神经生物学和矫形外科部门之间的合作将提供一个独特的多学科团队的方法来解决软骨修复的问题。只要能够获得大量特别资金，我们就处于进行这些研究的独特地位。这些研究将为该领域的研究人员提供一个全新的资源，并为了解软骨修复的遗传学提供资源。这些具有确定遗传学的动物模型将可供研究人员研究特定基因或基因组如何有助于软骨修复并因此导致OA的机制。对这一领域的投资将推动该领域的发展，使人们能够理解软骨修复，如果没有这个大机会，这个领域将处于休眠状态，因为“一次一个菌株”的方法将无法获得资金。在小鼠中发现的结果，一个适合遗传研究的物种，将立即适用于人类疾病，因为许多基因可能是相同的或影响相同的途径。从长远来看，对有助于软骨愈合的基因的理解可能会在OA发展到软骨退化之前很久就允许软骨的“内在”修复。参与维持软骨修复反应的参与者的知识将使我们能够确定哪些人更容易患OA。这可能会对公共卫生产生巨大影响，因为据估计，OA造成的疼痛和残疾影响了4000万人，每年损失30亿美元的工作和特殊护理费用。

DESCRIPTION (provided by applicant): This proposal is from Dr. Linda Sandell, a cartilage biologist in the Department of Orthopaedic Surgery and Dr. Jim Cheverud, a population geneticist in the Department of Anatomy and Neurobiology. We propose to identify genetically defined mouse models of cartilage healing. Recently, a direct correlation between articular cartilage healing and protection from osteoarthritis (OA) has been demonstrated. This will be a large-scale project that creates a unique resource for the study of the genes that contribute to cartilage healing and thus to OA. Dr. Cheverud currently uses "super-healing" mice for studies on genes that contribute to body size and has developed 12 inbred strains of mice containing portions of the genome and an advanced intercross between large (healing) and small (non-healing) mice of 40 generations. It has been demonstrated that the parental "super-healing" mice are able to regenerate cartilage significantly better than control mice. In the Department of Orthopaedic Surgery, we have established mouse models of fracture healing, cartilage healing and ligament healing and will perform full thickness cartilage wounds in the test animals. The collaboration between the Departments of Anatomy and Neurobiology and Orthopaedic Surgery would provide a unique multi-disciplinary team approach to the problem of cartilage repair. We are in a unique position to carry out these studies provided substantial special funding can be obtained. These studies will provide a completely new resource to investigators in the field and provide the resources to understand the genetics of cartilage repair. These animal models with defined genetics would be made available to investigators to study the mechanism of how a specific gene, or group of genes, contribute to cartilage repair and thus to OA. An investment in this area will catapult the field to allow for the understanding of cartilage repair, a field that, without this Grand Opportunity, will otherwise remain dormant in that funding for the "one strain at a time" approach will not be available. The results found in mice, a species that is amenable to genetic studies, will be immediately applicable to the human disease as many of the genes are likely to be the same or affect the same pathway. Long term, understanding of the genes that contribute to cartilage healing may allow for the "intrinsic" repair of cartilage long before OA develops to the point of cartilage degeneration. Knowledge of the players involved in sustaining a cartilage repair response will allow us to determine which individuals will be more susceptible to OA. This could have a huge public health impact as the pain and disability from OA is estimated to effect 40 million people and cost 3 billion dollars per year in work loss and special care.