Fueling left-right asymmetry: the role of glycolysis in stomach curvature

加剧左右不对称：糖酵解在胃曲率中的作用

• 批准号: 10605914
• 负责人: Nanette M Nascone-Yoder
• 金额: $ 22.47万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605914
• 关键词: Alcohol consumption; Amphibia; Anatomy; Binding Sites; Biological Assay; Candidate Disease Gene; Cell physiology; Cells; Complex; Congenital Abnormality; Data; Defect; Development; Embryo; Enzymes; Epithelium; Event; Gene Expression; Gene Order; Genes; Genus Hippocampus; Glucose; Glycolysis; Goals; Handedness; Homeostasis; Human; Individual; Left; Life; Mediating; Mesenchymal; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Morphogenesis; Morphology; Mutation; Organ; Organogenesis; Phenotype; Positioning Attribute; Publishing; Rana; Reagent; Regulation; Research; Respiration; Role; Shapes; Side; Situs Inversus; Smoking; Specific qualifier value; Stomach; Syndrome; Testing; Thinness; Transcript; Vertebrates; Work; Xenopus; Xenopus laevis; body system; cocaine use; epidemiology study; epithelial to mesenchymal transition; gain of function; gene function; inhibitor; knock-down; loss of function; malformation; mass spectrometric imaging; maternal diabetes; metabolomics; novel; pharmacologic; transcription factor; transcriptome sequencing; transcriptomic profiling

Project Summary Left-right (LR) differences in size, shape and/or anatomical position exist in almost every organ system. Consequently, abnormal LR asymmetry (known as heterotaxy, HTX) often leads to multiple, life threatening birth defects involving complex malformations and discordant laterality between organs. While the early embryonic events that establish global LR asymmetry have been well studied, it is the later-stage, organ- specific LR asymmetric morphogenesis events that are critical for normal anatomy; yet, for most organs, the molecular and cellular processes that sculpt their individual LR asymmetries have not been elucidated. This application will explore the novel and surprising concept that LR asymmetries in GLYCOLYSIS—the primordial metabolic pathway that breaks down glucose to generate ATP—are integrally involved in asymmetric organ morphogenesis. Published work has shown that leftward curvature of the stomach, an archetypical LR asymmetry conserved among vertebrates, depends on LR asymmetric rearrangements of mesenchymal cells into an epithelium (mesenchymal-to-epithelial transition; MET), causing thinning and expansion of the left stomach wall. Recent left vs right transcriptome profiling subsequently revealed that glycolysis enzymes are upregulated in the left side of the stomach during curvature. As glycolysis (as opposed to mitochondrial respiration) is known to promote epithelial-mesenchymal plasticity in other contexts, this unexpected finding raises the intriguing possibility that LR asymmetric glycolysis may facilitate the LR asymmetric MET that drives curvature morphogenesis. In the proposed project, this idea will be rigorously tested by exploiting the unique attributes of two different amphibian embryos, executing metabolomics, mass spectrometry imaging, glycolytic flux analyses, pharmacological perturbations, and left- vs right-targeted tests of gene function, to determine the function of glycolysis genes (Aim 1), and glycolytic metabolism (Aim 2) in stomach curvature morphogenesis. Successful completion of this R21 will therefore substantiate the intriguing premise that organ laterality is shaped by LR asymmetries in glycolysis, such that aberrant metabolic states may contribute to the development of laterality-related birth defects.

项目摘要 左右（LR）的大小，形状和/或解剖位置几乎存在于几乎每个器官系统中。 因此，异常的LR不对称性（称为异性疾病，htx）通常会导致多重生命威胁 生日缺陷涉及复杂的畸形和器官之间不一致的侧向。早些时候 建立全球LR不对称性的胚胎事件已经很好地研究了，它是后期的，有机体 对正常解剖学至关重要的特定LR非对称形态发生事件；但是，对于大多数器官来说， 尚未阐明雕刻其单个LR不对称的分子和细胞过程。这 应用将探讨糖酵解中LR不对称的新颖而令人惊讶的概念。 原始代谢途径分解葡萄糖以生成ATP，与 不对称器官形态发生。已发表的工作表明胃的向左弯曲， 脊椎动物之间配置的原型LR不对称性，取决于LR的非对称重排 间充质细胞进入上皮（间充质到上皮过渡； Met），导致变薄和 左Stallach墙的扩展。最近的左VS右转录组分析随后揭示了 曲率期间，糖酵解酶在stallch的左侧上调。作为糖酵解（如 已知与线粒体呼吸相反）在其他情况下会促进上皮 - 间质可塑性 这一意外发现提高了LR非对称糖酵解可能有助于LR的有趣可能性 不对称的符合曲率形态发生的情况。在拟议的项目中，这个想法将是严格的 通过利用两个不同的两栖胚胎的唯一属性测试，执行代谢组学，质量 光谱成像，糖酵解通量分析，药物扰动和左与右目标测试 基因功能的确定糖酵解基因的功能（AIM 1）和糖酵解代谢（AIM 2） 胃曲率形态发生。因此，成功完成此R21将证实有趣的 器官横向性在糖酵解中由LR不对称形成的前提，使得异常代谢 国家可能有助于发展与横向相关的先天缺陷的发展。