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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要几乎每个器官系统都存在大小、形状和/或解剖位置的左右（LR）差异。经过检查，异常的 LR 不对称性（称为异位性，HTX）通常会导致多种危及生命的疾病出生缺陷涉及复杂的畸形和器官之间不协调的偏侧性。建立全局 LR 不对称性的胚胎事件已得到充分研究，它是后期的器官- 对正常解剖结构至关重要的特定 LR 不对称形态发生事件；塑造其个体 LR 不对称性的分子和细胞过程尚未阐明。应用程序将探索糖酵解中 LR 不对称性这一新颖且令人惊讶的概念—— 分解葡萄糖产生 ATP 的原始代谢途径——完整地参与已发表的研究表明，胃向左弯曲是一种不对称的器官形态发生。脊椎动物中保守的典型 LR 不对称性取决于 LR 不对称重排间充质细胞转化为上皮细胞（间充质到上皮细胞的转变；MET），导致细胞变薄和最近的左胃壁扩张与右转录组分析随后表明：糖酵解过程中，胃左侧的糖酵解酶上调（如。与线粒体呼吸相反）已知可以在其他情况下促进上皮间质可塑性，这一意外的发现提出了一个有趣的可能性，即 LR 不对称糖酵解可能促进 LR 驱动曲率形态发生的不对称 MET 在拟议的项目中，这个想法将得到严格的体现。通过利用两种不同两栖动物胚胎的独特属性、执行代谢组学、质量进行测试光谱成像、糖酵解通量分析、药理学扰动以及左靶向测试和右靶向测试基因功能，以确定糖酵解基因（目标 1）和糖酵解代谢（目标 2）的功能因此，R21 的成功完成将证实这一有趣的发现。前提是器官偏侧性是由糖酵解中 LR 不对称性形成的，因此异常代谢国家可能会导致与偏侧相关的出生缺陷的发生。