Type XXVII Collagen in Late-onset Bone Deformity

晚发性骨畸形中的 XXVII 型胶原蛋白

• 批准号: 7714349
• 负责人: Helena Telfer
• 金额: $ 1.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714349
• 关键词: Address; Adult; Affect; Aging; Bone Density; Bone Development; Bone Matrix; Bone Regeneration; Bone Surface; Cartilage; Collagen; Collagen Gene; Defect; Deformity; Deposition; Development; Developmental Process; Diagnostic radiologic examination; Embryo; Embryonic Development; Event; Extracellular Matrix; Fibrillar Collagen; Fishes; Foundations; Fracture; Future; Genes; Genetic; Genetic Translation; Health; Human; In Situ Hybridization; In Vitro; Intervertebral disc structure; Ligaments; Link; Microscopy; Minerals; Modeling; Molecular; Morphogenesis; Pathogenesis; Phenotype; Population; Predisposition; Proteins; Proteoglycan; Quality of life; Role; Scanning Electron Microscopy; Somites; Spinal; Staging; Staining method; Stains; Swimming; Tail; Techniques; Testing; Time; Transcript; Transmission Electron Microscopy; United States; Vertebral column; Zebrafish; base; bone; craniofacial; experience; flexibility; mineralization; notochord; notochord development; scaffold; scoliosis; spine bone structure; therapy design

DESCRIPTION (provided by applicant): In aging populations of the United States and elsewhere, spinal deformity and bone fragility are two common conditions that threaten quality of life. To clinically address these health concerns requires a clear understanding of bone development. Fibrillar collagens are scaffolds for bone deposition and remodeling and promote bone regeneration in vitro. We identified the type XXVII collagen gene, col27a1 that encodes a fibrillar collagen expressed in human developing cartilage. Preliminary studies in zebrafish indicate that col27a1 is expressed in the notochord during early development and in the cartilage anlagen of bone. Inhibition of col27a1 mRNA translation results in a late scoliosis phenotypein mildly affected embryos and defective somite development and loss of tail elongation in severely affected embryos. I hypothesize that knockdown of col27a1 during embryonic development alters the ultrastructural organization of the notochord, resulting in adult scoliosis. I will examine early notochord development and determine the progression of pathogenesis through adulthood. I will also determine if other notochord-specific genes are abnormally regulated in affected fish and identify ultrastructural changes in the mature vertebral column responsible for spinal deformation. This study will provide a foundation for future translational applications by testing the role of col27a1 in susceptibility to scoliosis and by exploring the critical link between early developmental processes and late-onset dysmorphogenesis. Relevance: Spinal deformity is a common condition in aging adults, but our understanding of the mechanisms involved in development of these conditions is limited. This study will investigate a genetic mechanism involved in development degenerative scoliosis, providing a basis for design of treatments targeting scoliosis and related conditions.

描述（由申请人提供）：在美国和其他地方的老龄化人口中，脊柱畸形和骨脆性是威胁生活质量的两种常见疾病。为了在临床上解决这些健康问题，需要对骨骼发育有一个清晰的认识。纤维性胶原是骨沉积和骨重塑的支架，在体外促进骨再生。我们发现了XXVII型胶原蛋白基因col27a1，该基因编码在人类发育软骨中表达的纤维胶原蛋白。对斑马鱼的初步研究表明，col27a1在发育早期的脊索和骨的软骨胶原中表达。col27a1 mRNA翻译的抑制导致轻度受影响胚胎的晚期脊柱侧弯表型，严重受影响胚胎的体体发育缺陷和尾巴延长的丧失。我推测，在胚胎发育期间col27a1的下调改变了脊索的超微结构组织，导致成人脊柱侧凸。我将检查脊索的早期发展，并确定成年后发病机制的进展。我还将确定其他脊索特异性基因是否在受影响的鱼类中受到异常调节，并确定导致脊柱变形的成熟脊柱的超微结构变化。该研究将通过测试col27a1在脊柱侧凸易感性中的作用，以及探索早期发育过程与迟发性畸形发生之间的关键联系，为未来的转化应用奠定基础。相关性：脊柱畸形是老年人的一种常见疾病，但我们对这些疾病发展的机制了解有限。本研究将探讨退行性脊柱侧凸发生的遗传机制，为设计针对脊柱侧凸及相关疾病的治疗方法提供依据。