Elucidating the Cellular and Molecular Mechanisms of Late-Onset Scoliosis

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，通常需要进行医疗干预，如支具或手术。尽管对儿童、父母和卫生保健系统造成了重大负担，但对AIS的病因了解甚少。部分原因是缺乏遗传学上易于处理的脊柱侧凸动物模型。基于这个原因，我将研究一种新的显性插入斑马鱼突变体druk中轴弯曲形成和发展的细胞和分子机制。有趣的是，druk显示可能的推论人类AIS，如渐进的曲率的轴柱没有畸形的椎骨开始在幼虫阶段。我已经确定，两个基因，mon 1a和mstr 1 rb，直接侧翼的druk插入表现出转录上调druk突变鱼。我假设druk产生一个或两个侧翼基因的分子功能获得。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腋弯曲。已经提出了AIS的多种机制，包括沿着轴柱的肌腱连接沿着的损失以及骨矿物质密度（BMD）的普遍损失。X射线显微断层扫描（<$-CT）分析成年druk鱼显示了显着减少BMD的轴柱。我推测骨代谢异常可能先于药物引起的轴弯曲的进展。为了验证这一点，我将询问破骨细胞、成骨细胞的活性或沿中轴沿着的肌腱连接的异常发育是否有助于druk突变表型。这项建议的目的是定义的起源和发展的遗传听话的轴柱弯曲的斑马鱼幼虫，类似于AIS在人类的特征的细胞和分子机制。这些结果可能提供脊柱侧凸位点的遗传学证据，这将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学的理解，并可能作为开发新的药物疗法以对抗人类AIS的模型。

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.