Developmental Mechanisms of Human Idiopathic Scoliosis

项目概要/摘要（总体） 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 疼痛和生理功能障碍。需要治疗AIS的女孩人数超过男孩， 五倍，原因不明。在美国，AIS的医院费用每年超过10亿美元。 并且比其他儿科手术增长得更快。AIS的治疗是手术治疗，而不是 因为对潜在的病因学知之甚少。遗传因素对AIS的影响 在本计划开始之前，虽然发现了一些重要的人类易感基因座，但却很少。的 由这些基因座驱动的机制同样在很大程度上是未知的，因为它们在非编码基因组中定位， 不容易解释的区域。AIS领域也缺乏适当的动物模型， 机制和治疗研究。为了解决这些问题，我们建立了一个创新的合作伙伴关系， 结合三个项目的方法，以引导人类无偏见的基因发现，建模和基因发现 以及出生后脊椎发育的基因组分析。我们的计划解决了六个差距， 知识：（i）AIS的组织和细胞起源的身份;（ii）定义AIS疾病的真正开始 发病机制;（iii）定义AIS的遗传因素和遗传相互作用;（iv）制定稳健的 脊椎动物系统功能验证，解释和模拟人类遗传发现;（v）定义 控制体节发生后脊髓发育的分子机制，以及与AIS的相关性;（vi） 确定AIS中两性异形的基础。在上一个授予周期中，我们的计划取得了显著进展 每一项举措。整合人类和动物模型的数据，我们的数据强调软骨是一种 AIS中的功能组织，并特别强调了细胞外基质室，在AIS的新范例， 领域我们的项目在人类中发现了几个新的AIS遗传易感位点，并培育了73条新的斑马鱼 脊柱畸形的模型。来自每个项目的数据也集中在AIS疾病等位基因的亚型性质上， 支持多基因遗传。我们定义了人类和小鼠AIS相关的非编码调控景观， 组织，并发现敲除一个与人类女性AIS相关的调节因子， 表型在这里，我们提出了一个全面的计划，以推动这些发现，以确定AIS疾病 使用遗传靶向小鼠和斑马鱼模型的机制，以定义细胞特异性转录，表观遗传， AIS潜在的信号传导机制，继续通过正向遗传学方法识别脊柱畸形的脊椎动物模型， 在小鼠和斑马鱼中进行筛选，并在难治性患者中发现导致AIS的新的高危等位基因。 我们还将扩大我们的调查，以解决为什么AIS有女性偏见，并测试合理选择的药物， 脊椎动物模型中的治疗方法。这些研究将促进对AIS的基本理解，为诊断提供信息， 突出潜在治疗靶点。

Project Summary/Abstract (Overall) 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 physiologic dysfunction later in life. Girls requiring treatment for AIS outnumber boys by more than five-fold, for reasons that are unknown. Hospital charges for AIS surpass one billion dollars annually in the U.S. and are rising significantly faster than for other pediatric procedures. AIS is treated symptomatically rather than preventively because the underlying etiology has been poorly understood. Genetic contributions to AIS are significant, but few human susceptibility loci were identified prior to the beginning of this Program. The mechanisms driven by these loci were likewise largely unknown, as they mapped within non-coding genomic regions that were not easily interpreted. The AIS field also lacked appropriate animal models that enable mechanistic and therapeutic studies. To address these issues, we established an innovative collaborative approach combining three Projects to lead unbiased gene discovery in humans, modeling and gene discovery in zebrafish, and genomic analysis of postnatal spine development. Our program addressed six gaps in knowledge: (i) identity of the tissue and cellular origins of AIS; (ii) defining the true beginning of AIS disease pathogenesis; (iii) defining the genetic factors and genetic interactions underlying AIS; (iv) developing robust vertebrate systems to functionally validate, interpret, and model human genetic findings; (v) defining the molecular mechanisms controlling spinal development post-somitogenesis, and the correlation with AIS; (vi) defining the basis of sexual dimorphism in AIS. In the prior award cycle our Program significantly advanced each of these initiatives. Integrating data in humans and animal models, our data underscored cartilage as a functional tissue in AIS and specifically highlighted the extracellular matrix compartment, new paradigms in the field. Our Program discovered several new AIS genetic susceptibility loci in human and developed 73 new zebrafish models of spine deformity. Data from each Project also converged on the hypomorphic nature of AIS disease alleles, supporting multigenic inheritance. We defined the non-coding regulatory landscape of human and mouse AIS-related tissues, and discovered that knockout of one such regulator linked to female AIS in humans produces a female-biased phenotype in mouse. Here we propose a comprehensive plan to drive these discoveries forward to define AIS disease mechanisms using genetically targeted mouse and zebrafish models, to define cell-specific transcriptional, epigenetic, and signaling mechanisms underlying AIS, to continue identifying vertebrate models of spine deformity by forward genetic screens in mouse and zebrafish, and to discover new high-risk alleles contributing to AIS in patients refractory to treatment. We will also expand our investigations to address why AIS has a female bias, and to testing rationally selected drug therapies in vertebrate models. These studies will advance fundamental understanding of AIS, inform diagnosis and highlight potential therapeutic targets.