Developmental Mechanisms of Human Idiopathic Scoliosis

项目摘要/摘要 青少年特发性脊柱侧凸(AIS)是一种脊柱扭曲的疾病，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、背痛的风险 疼痛，以及晚年的肺功能障碍。需要治疗AIS的女孩比男孩多 五个方面，原因不详。对认可机构采取的是症状治疗而不是预防性治疗，因为 潜在的病因尚不清楚。在美国，AIS的医院费用每年超过10亿美元， 比其他儿科手术上升得更快。我们的总体目标是了解 AIS的生物病因作为早期诊断、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) 我们小组和其他人的常见非编码变体已经确定了与AIS相关的单倍型，但 这些协会的机制基础仍有待界定。此外，这些发现解释的不是 总遗传力的5%，部分原因是AIS外显子尚未完全被询问。另一个 理解人类AIS发病机制的障碍一直是缺乏适当的、遗传的- 已定义的动物模型对于定义疾病的时空参与是必不可少的。最后是 出生后脊柱发育的一般发育规律和AIS的特定起源组织 具体地说，人们对此知之甚少。为了解决这些问题，我们建立了一个创新的协作 将人类无偏见的基因发现、斑马鱼的建模和基因发现相结合的方法，以及 出生后脊柱发育的基因组分析。具体地说，我们建议的组成部分活动 该计划将协同产生AIS研究领域所缺乏的工具和基础知识， 解决以下目标：(1)我们将传递AIS易感性的遗传结构定义为 (2)我们将开发第一个遗传易驯化的脊椎动物系统，用于 建立AIS模型并研究在人类中发现的AIS突变的功能后果；(3)我们将 定义AIS因果基因的顺式和反式调控；(4)我们将试点大规模基因组学平台 表征控制脊柱发育的分子机制；(5)我们将鉴定和表征 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 我们将推动创新努力，为AIS开发新的治疗方法。我们的发现将 推动该领域朝着亟需的假说驱动的研究方向发展，旨在早期分子诊断、预防 和治疗。我们还期待这些研究将启发人类的其他结构缺陷。

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.