Establishing Left-Right Asymmetry in Vertebrates

建立脊椎动物的左右不对称性

• 批准号: 8440330
• 负责人: Cammon ARRINGTON
• 金额: $ 13.71万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440330
• 关键词: Binding; Biological Models; Cardiac; Cardiovascular system; Cells; Child; Cilia; Complex; Congenital Heart Defects; Defect; Detection; Development; Extracellular Fluid; Gastrula; Gene Expression; Genes; Genetic; Handedness; Heart; Heparan Sulfate Proteoglycan; Human; Lateral; Lead; Left; Mesoderm; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Morphogenesis; Mus; Nodal; Organ; Organogenesis; Pathway interactions; Pattern; Play; Positioning Attribute; Process; Role; Side; Structure; System; Testing; Tube; Vertebrates; Vesicle; Zebrafish; base; cilium biogenesis; congenital heart disorder; epithelial to mesenchymal transition; fibroglycan; fluid flow; improved; malformation; mortality; precursor cell; public health relevance

DESCRIPTION (Provided by Applicant): Strong conservation of heart formation along the left-right (LR) axis among vertebrates suggests that common developmental mechanisms and genetic pathways exist for left-right development. However, despite abundant evidence supporting a role for nodal monocilia in the establishment of LR asymmetry, little is known about formation of the late gastrula node. In zebrafish, the node equivalent is Kupffer's vesicle (KV). KV contains monocilia, generates asymmetric fluid flow, and is necessary for left-sided expression of downstream laterality genes. Because KV is easily visualized and experimentally manipulated in zebrafish, the candidate will use this model system to better understand KV formation and its role in LR development. From preliminary studies, he has discovered that syndecan-2, a single-pass transmembrane heparan sulfate proteoglycan, is required for normal LR development and plays a cell-autonomous role in KV formation. Morpholino knockdown of syndecan-2 causes reversal of heart and gut looping and leads to misshapen KV with fewer and shorter cilia. Based on these observations, the candidate proposes to further define the role of syndecan-2 in KV and cilia formation/function and explore the necessary molecular interactions of syndecan-2 during the process of KV development. Through this study, genetic and molecular mechanisms that regulate cardiac LR development will be discovered and one day used to improve detection and treatment of congenital heart disease in children.

描述（申请人提供）：脊椎动物中心脏形成沿左右（LR）轴沿着的强保守性表明左右发育存在共同的发育机制和遗传途径。 然而，尽管有大量的证据支持的作用，节点单纤毛在LR不对称的建立，很少有人知道的形成后期原肠胚节点。 在斑马鱼中，节点等同物是库普弗囊泡（KV）。 KV含有单纤毛，产生不对称的流体流动，并且是下游偏侧性基因的左侧表达所必需的。 由于KV在斑马鱼中很容易可视化和实验操作，候选人将使用这个模型系统来更好地了解KV的形成及其在LR发展中的作用。 从初步研究中，他发现syndecan-2是一种单通道跨膜硫酸乙酰肝素蛋白聚糖，是正常LR发育所需的，并在KV形成中发挥细胞自主作用。 Morpholino敲低syndecan-2导致心脏和肠循环逆转，并导致纤毛更少更短的畸形KV。 基于这些观察结果，候选人建议进一步确定syndecan-2在KV和纤毛形成/功能中的作用，并探索在KV发育过程中syndecan-2的必要分子相互作用。 通过这项研究，调节心脏LR发育的遗传和分子机制将被发现，并有一天用于改善儿童先天性心脏病的检测和治疗。