Genetic Mouse Models of Cartilage Healing

软骨愈合的基因小鼠模型

• 批准号: 7853233
• 负责人: JAMES M CHEVERUD
• 金额: $ 66.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7853233
• 关键词: Affect; Age; Anatomy; Animal Model; Animal Testing; Animals; Applications Grants; Area; Autopsy; Body Size; Caring; Cartilage; Chromosome Mapping; Chromosomes; Collaborations; DNA; Data; Degenerative polyarthritis; Ear; Family; Female; Fracture Healing; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Models; Genetic Recombination; Genetic Variation; Genome; Genotype; Goals; Harvest; Healed; Heritability; Histology; Human; Inbred Strain; Inbred Strains Mice; Individual; Inherited; Investments; Joints; Knee; Knowledge; Laboratories; Ligaments; Liver; MRL/MpJ Mouse; Maps; Measures; Modeling; Mouse Strains; Mus; Natural regeneration; Neurobiology; Operative Surgical Procedures; Orthopedic Surgery procedures; Pain; Pathway interactions; Phenotype; Population; Positioning Attribute; Public Health; Quantitative Genetics; RNA; RNA analysis; Research Personnel; Resistance; Resources; Sample Size; Specimen; Staining method; Stains; Surveys; Testing; Thick; Time; Tissues; Traumatic Arthropathy; Variant; Work; Wound Healing; age related; articular cartilage; base; cost; disability; genetic analysis; genetic strain; genome-wide; healing; high throughput analysis; human disease; juvenile animal; male; mouse model; repaired; research study; response; sex; wound

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.

描述（由申请人提供）：本提案来自骨科软骨生物学家Linda Sandell博士和解剖学与神经生物学家Jim Cheverud博士。我们建议鉴定基因定义的小鼠软骨愈合模型。最近，关节软骨愈合和保护骨性关节炎（OA）之间的直接关系已被证实。这将是一个大规模的项目，为研究有助于软骨愈合的基因创造一个独特的资源，从而有助于OA。Cheverud博士目前使用“超级愈合”小鼠研究影响体型的基因，并开发了12种近交系小鼠，其中包含部分基因组，并在40代的大（愈合）和小（不愈合）小鼠之间进行了高级杂交。研究表明，亲代“超愈合”小鼠的软骨再生能力明显优于对照小鼠。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，并将在实验动物上进行全层软骨损伤。解剖学、神经生物学和矫形外科之间的合作将为软骨修复问题提供独特的多学科团队方法。如果能够获得大量的特别资金，我们在进行这些研究方面处于独特的地位。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。这些具有明确遗传学的动物模型将提供给研究人员，以研究特定基因或基因组如何促进软骨修复从而促进OA的机制。对这一领域的投资将推动这一领域的发展，使人们对软骨修复有了更深入的了解。如果没有这个重大机遇，这一领域将会一直处于休眠状态，因为“一次一种”的方法将无法获得资金。在老鼠身上发现的结果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，对促进软骨愈合的基因的理解可能允许在OA发展到软骨退变点之前很久进行软骨的“内在”修复。了解参与维持软骨修复反应的球员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OA造成的疼痛和残疾估计影响到4000万人，每年损失30亿美元的工作和特殊护理费用。