Elucidating the Cellular and Molecular Mechanisms of Late-Onset Scoliosis

阐明迟发性脊柱侧凸的细胞和分子机制

• 批准号: 8654501
• 负责人: Ryan Scott Gray
• 金额: $ 5.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8654501
• 关键词: Adolescent; Adult; Affect; Alleles; Animal Model; Appearance; Beryllium; Biological Models; Biomechanics; Bone Density; Braces-Orthopedic appliances; Candidate Disease Gene; Characteristics; Child; Childhood; Connective Tissue; Defect; Deformity; Development; Dissection; Distal; Early Diagnosis; Enhancers; Etiology; Excision; Exhibits; Fertilization; Fishes; Foundations; Functional disorder; Future; Generations; Genes; Genetic; Genetic Models; Genetic Screening; Healthcare Systems; Human; Idiopathic scoliosis; Individual; Intervention; Joints; Knowledge; Larva; Lateral; Link; Location; Longitudinal Studies; Maintenance; Mechanics; Medical; Methods; Modeling; Molecular; Muscle; Musculoskeletal; Musculoskeletal System; Mutation; Neurologic; Operative Surgical Procedures; Oryctolagus cuniculus; Osteoblasts; Osteoclasts; Osteopenia; Parents; Patients; Phenotype; Puberty; Roentgen Rays; School-Age Population; Site; Skeletal Development; Skeleton; Spinal; Spinal Curvatures; Staging; Syndrome; Tendon structure; Testing; Tissues; Translating; Up-Regulation; Vertebral column; Zebrafish; bone; bone metabolism; combat; gain of function; genetic pedigree; genome wide association study; insight; interest; malformation; model development; mutant; neuromuscular; novel; overexpression; research study; rib bone structure; scoliosis; spine bone structure; transmission process; zebrafish development

DESCRIPTION (provided by applicant): Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity, which affects 2-3% of school age children and often necessitates medical intervention such as bracing or surgery. Despite a significant burden to children, parents and health care systems; the etiology of AIS is poorly understood. In part, this is due to a lack of genetically tractable animal models of scoliosis. For this reason, I will investigate cellular and molecular mechanisms of the formation and progression of axial curvatures in a novel dominant insertional zebrafish mutant, druk. Interestingly, druk displays possible corollaries to human AIS such as progressive curvature of the axial column without malformation of vertebrae beginning at larval stages. I have determined that two genes, mon1a and mstr1rb, immediately flanking the druk insertion exhibit transcriptional upregulation in druk mutant fish. I hypothesize that druk produces a molecular gain-of-function of one or both flanking genes. I will directly test if overexpression of these genes is sufficient to generate axil curvatures in larval fish. Multiple mechanisms have been proposed for AIS including loss of myotendenous connections along the axial column as well as generalized loss of bone mineral density (BMD). X-ray microtomography (¿-CT) analysis of adult druk fish showed a significant decrease in BMD of the axial column. I hypothesize that abnormal bone metabolism may precede the progression of druk induced axial curvature. To test this, I will ask if the activity o osteoclasts, osteoblasts or the abnormal development of myotendinous junctions along the axial column contributes to the druk mutant phenotype. This proposal aims to define the cellular and molecular mechanisms of the origin and progression of genetically tractable axial column curvatures in a larval zebrafish, akin to characteristics of AIS in humans. These results may provide genetic evidence of a scoliosis locus that will assist early detection in humans. Finally, the druk mutant will enhance our understanding of the etiology of scoliosis and possibly serve as a model for the development of novel pharmacological therapies to combat AIS in humans.

描述（由申请人提供）：青少年特发性脊柱侧凸 (AIS) 是最常见的儿科脊柱畸形，影响 2-3% 的学龄儿童，通常需要医疗干预，例如支具或手术，尽管这给儿童和家长带来了很大的负担。和医疗保健系统；对 AIS 的病因知之甚少，部分原因是缺乏遗传上可控制的脊柱侧凸动物模型。以及新型显性插入斑马鱼突变体 druk 中轴向弯曲形成和进展的分子机制，druk 有意向人类 AIS 展示了可能的推论，例如从幼虫阶段开始没有椎骨畸形的轴向柱弯曲。紧邻 druk 插入侧翼的两个基因 mon1a 和 mstr1rb 在 druk 突变鱼中表现出转录上调。我将直接测试这些基因的过度表达是否足以在幼鱼中产生轴曲率，其中包括沿轴柱和肌腱连接的丧失。骨矿物质密度（BMD）普遍丧失。 -CT）对成年德鲁克鱼的分析显示，轴柱的骨密度显着下降，我认为骨代谢异常可能先于德鲁克引起的轴曲度的进展，为了测试这一点，我会问破骨细胞、成骨细胞或成骨细胞的活性是否存在。沿轴柱肌腱连接的异常发育导致了 druk 突变表型。该提案旨在定义遗传易处理轴柱的起源和进展的细胞和分子机制。斑马鱼幼虫的弯曲程度与人类 AIS 的特征相似，这些结果可能提供脊柱侧凸位点的遗传证据，有助于人类的早期发现。最后，druk 突变体将增强我们对脊柱侧凸病因的理解。开发对抗人类 AIS 的新型药物疗法的模型。