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: 7541054
• 负责人: Helena Telfer
• 金额: $ 3.3万
• 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 2010-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541054
• 关键词: Address; Adult; Affect; Aging; Bone Density; Bone Development; Bone Matrix; Bone Regeneration; Bone Surface; Bone and Cartilage Funding; Cartilage; Collagen; Collagen Gene; Condition; 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; Pliability; Population; Predisposition; Proteins; Proteoglycan; Quality of life; Rate; 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; mineralization; notochord; 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）：在美国和其他地区的老龄化人口中，脊柱畸形和骨骼脆弱是威胁生活质量的两种常见状况。要在临床上解决这些健康问题，需要对骨骼发育有清晰的了解。纤维状胶原蛋白是骨沉积和重塑的支架，并在体外促进骨再生。我们鉴定出 XXVII 型胶原蛋白基因 col27a1，它编码在人类发育软骨中表达的纤维状胶原蛋白。对斑马鱼的初步研究表明，col27a1 在早期发育过程中的脊索和骨的软骨原基中表达。抑制 col27a1 mRNA 翻译会导致轻度影响胚胎的晚期脊柱侧凸表型，以及严重影响胚胎的体节发育缺陷和尾部伸长损失。我推测胚胎发育过程中 col27a1 的敲低会改变脊索的超微结构组织，导致成人脊柱侧凸。我将检查早期脊索发育并确定成年期发病机制的进展。我还将确定受影响的鱼类中其他脊索特异性基因是否受到异常调节，并确定导致脊柱变形的成熟脊柱的超微结构变化。这项研究将通过测试 col27a1 在脊柱侧凸易感性中的作用以及探索早期发育过程和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常见病症，但我们对这些病症发生机制的了解有限。这项研究将调查退行性脊柱侧凸发育中涉及的遗传机制，为设计针对脊柱侧凸和相关病症的治疗方法提供基础。