Developmental Mechanisms of Human Idiopathic Scoliosis

人类特发性脊柱侧凸的发育机制

• 批准号: 9150821
• 负责人: Nadav Ahituv
• 金额: $ 154.56万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150821
• 关键词: Address; Adolescent; Affect; Animal Model; Architecture; Back Pain; Biological; Biological Assay; Biological Models; CRISPR/Cas technology; Candidate Disease Gene; Cartilage; ChIP-seq; Child; Childhood; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Coupled; Data Set; Deformity; Development; Disease; Disease model; Early Diagnosis; Engineering; Enhancers; Etiology; Family member; Functional disorder; Future; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Screening; Genomics; Goals; Haplotypes; Hereditary Disease; Heritability; Heterogeneity; Hospital Charges; Human; Idiopathic scoliosis; Induced Mutation; Infection; Investigation; Kinesin; Knowledge; Lead; Life; Life Style; Literature; Lung; Malignant Neoplasms; Massive Parallel Sequencing; Medical; Methods; Modeling; Molecular; Molecular Diagnosis; Musculoskeletal Diseases; Mutation; Names; Nucleic Acid Regulatory Sequences; Obesity; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Phenotype; Play; Population; Positioning Attribute; Predisposition; Prevention; Prevention therapy; Procedures; Reagent; Regulation; Regulatory Element; Research; Research Personnel; Risk; School-Age Population; Solid; Spinal; Structural defect; System; Technology; Testing; Time; Tissues; Untranslated RNA; Validation; Variant; Vertebral column; Work; Zebrafish; abstracting; base; boys; cohort; cost efficient; exome; gene discovery; genome editing; genome sequencing; genome wide association study; genomic platform; girls; innovation; male; mouse genome; mutant; mutational status; novel; novel therapeutics; null mutation; postnatal; prevent; proband; programs; sequencing platform; sex; spatiotemporal; tool; transcription activator-like effector nucleases; transcriptome sequencing; whole genome

Project Summary/Abstract Adolescent idiopathic scoliosis (AIS) is a twisting condition of the spine and is the most common pediatric musculoskeletal disorder, affecting 3% of children worldwide. Children with AIS risk severe disfigurement, back pain, and pulmonary dysfunction later in life. Girls requiring treatment for AIS outnumber boys by more than five-fold, for reasons that are unknown. AIS is treated symptomatically rather than preventively because the underlying etiology is unknown. Hospital charges for AIS surpass one billion dollars annually in the U.S. and are rising significantly faster than for other pediatric procedures. Our overall purpose is to understand the biologic causes of AIS as a means to early diagnosis, prevention and non-invasive biologic treatment. Adolescent idiopathic scoliosis is a complex genetic disease. Genome wide association studies (GWAS) of common non-coding variants by our group and others have identified AIS-associated haplotypes, but the mechanistic basis of these associations remains to be defined. Furthermore these findings explain less than 5% of overall heritability due in part to the fact that the AIS exome has yet to be fully interrogated. Another barrier to understanding the pathogenesis of AIS in humans has been the lack of appropriate, genetically- defined animal models that are essential for defining spatiotemporal involvement in the disease. Finally the developmental regulation of postnatal spinal development generally, and the specific tissue of origin in AIS specifically, are poorly understood. To address these issues we have established an innovative collaborative approach combining unbiased gene discovery in humans, modeling and gene discovery in zebrafish, and genomic analysis of postnatal spine development. Specifically, the component activities of our proposed Program will synergize to yield the tools and fundamental knowledge that the field of AIS research has lacked, addressing the following goals: (1) We will define the genetic architecture conveying AIS susceptibility as identified in human populations; (2) We will develop the first genetically tractable vertebrate system for modeling AIS and studying the functional consequences of AIS mutations identified in humans; (3) We will define cis-and trans-regulation of AIS causal genes; (4) We will pilot a large-scale genomics platform to begin to characterize the molecular mechanisms controlling spinal development; (5) We will identify and characterize causal mutations in patients that may identify gene-based AIS subtypes; (6) By filling gaps in fundamental knowledge of the disease we will drive innovative efforts to develop new therapies for AIS. Our discoveries will spur the field toward much-needed hypothesis-driven research aimed at early molecular diagnosis, prevention and therapies. We also expect that these studies will enlighten other structural defects of humans.

项目总结/摘要 青少年特发性脊柱侧凸（AIS）是一种脊柱扭曲的情况，是最常见的儿科疾病， 肌肉骨骼疾病，影响全球3%的儿童。患有AIS的儿童有严重毁容的风险，背部 疼痛和肺功能障碍需要治疗AIS的女孩人数超过男孩， 五倍，原因不明。AIS是治疗性的，而不是预防性的，因为 潜在病因不明。在美国，AIS的医院费用每年超过10亿美元， 比其他儿科手术增长得更快。我们的总体目标是了解 AIS的生物学原因作为早期诊断、预防和非侵入性生物治疗的手段。 青少年特发性脊柱侧凸是一种复杂的遗传性疾病。全基因组关联研究（GWAS） 我们的研究小组和其他人已经确定了常见的非编码变异与AIS相关的单倍型，但是 这些关联的机制基础仍有待确定。此外，这些发现解释了不到 5%的整体遗传率，部分原因是AIS外显子组尚未完全被询问。另一 理解人类AIS发病机制的障碍是缺乏适当的，遗传学上的， 定义的动物模型，这是必不可少的定义时空参与疾病。最后 出生后脊柱发育的一般发育调节，以及AIS中起源的特定组织 具体来说，人们对它知之甚少。为了解决这些问题，我们建立了一个创新的合作伙伴关系， 结合人类无偏基因发现、斑马鱼建模和基因发现的方法，以及 出生后脊柱发育的基因组分析。具体而言，我们建议的 该计划将协同产生AIS研究领域缺乏的工具和基础知识， 解决以下目标：（1）我们将定义表达AIS易感性的遗传结构， （2）我们将开发第一个遗传上易于处理的脊椎动物系统， 建立AIS模型并研究在人类中鉴定的AIS突变的功能后果;（3）我们将 明确AIS致病基因的顺式和反式调控;（4）我们将试点一个大规模的基因组学平台，开始 以表征控制脊柱发育的分子机制;（5）我们将识别和表征 患者中可能识别基于基因的AIS亚型的因果突变;（6）通过填补基础研究的空白， 我们将推动创新努力，为AIS开发新的疗法。我们的发现将 刺激该领域向急需的假设驱动的研究，旨在早期分子诊断，预防， 和治疗。我们也期望这些研究能启发人类的其他结构缺陷。