Metabolism and Malrotation

新陈代谢和旋转不良

基本信息

批准号：
10646987
负责人：
Nanette M Nascone-Yoder
金额：
$ 7.27万
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：
2023-03-06 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646987
关键词：
Abnormal Cell Affect Animal Model Animals Architecture Area Atrazine Behavior Biological Assay Birth Cell division Cells Chloroplasts Complex Congenital Abnormality Data Defect Development Disease Electron Transport Embryo Epithelium Etiology Event Exposure to Frequencies Gastrointestinal tract structure Generations Genetic Genus Hippocampus Glycolysis Glycolysis Pathway Herbicides Human Intestines Length Life Mass Spectrum Analysis Mediating Metabolic Metabolism Methodology Mitochondria Modeling Morbidity - disease rate Morphogenesis Nuclear Operative Surgical Procedures Organ Oxidative Phosphorylation Pathogenesis Patients Plants Pregnancy Process Reaction Respiration Role Rotation Structural Congenital Anomalies Surface Technology Testing Therapeutic Tissues Toxic Environmental Substances Toxin Xenopus epithelial to mesenchymal transition fetal innovation insight mass spectrometric imaging metabolomics migration nutrition pharmacologic spatiotemporal transcriptome sequencing

项目摘要

Project Summary/Abstract Intestinal malrotation (IM) is a highly prevalent birth defect that can lead to life-threatening conditions necessitating surgical intervention and long-term supplemental nutrition. Atrazine (ATR), a ubiquitous herbicide that perturbs electron transport chain (ETC) reactions, was found to cause IM at high frequency. Preliminary data show that ATR decreases mitochondrial respiration (i.e., oxidative phosphorylation; oxphos) and increases glycolytic activity in the developing intestine. However, while early gut development can subsist on glycolysis alone, later gut development requires oxphos; thus, ATR may block a critical metabolic switch from glycolysis to mitochondrial respiration (oxphos) during intestine morphogenesis. During normal gut development, intestinal rotation occurs simultaneously with gut lengthening, and shorter gut lengths are often associated with IM, suggesting that gut elongation mechanisms are integral to the rotation process. Indeed, cellular analyses reveal that ATR perturbs crucial events required to drive intestinal lengthening, including early mesenchymal-to-epithelial transitions (MET) and, later, interkinetic nuclear migration (IKNM) -- common morphogenetic processes recently found to be influenced by cellular metabolic states. Together, these data suggest that a metabolic switch from glycolysis to oxphos drives proper intestine rotation by regulating the timing and/or localization of MET and IKNM events during gut elongation. This hypothesis will be tested using innovative metabolomics technologies to determine: 1) how ATR affects the spatiotemporal dynamics of cellular metabolism during intestine morphogenesis, and 2) how dynamic cellular metabolic states affect the timing and localization of MET and IKNM within the developing intestine. Successful completion of these aims will illuminate the poorly understood etiology of IM, and will have implications for the role of metabolism-altering toxins, diseases, and/or pregnancy conditions in the development of structural birth defects that depend on MET- and/or IKNM-mediated morphogenesis.

项目概要/摘要肠旋转不良 (IM) 是一种非常普遍的出生缺陷，可能导致危及生命的情况需要手术干预和长期补充营养。阿特拉津（ATR），一种普遍存在的除草剂扰乱电子传递链 (ETC) 反应，被发现会在高频率下引起 IM。初步的数据显示，ATR 会降低线粒体呼吸（即氧化磷酸化；oxphos）并增加发育中肠道的糖酵解活性。然而，虽然早期肠道发育可以依靠糖酵解来维持单独而言，后期肠道发育需要氧化磷；因此，ATR 可能会阻断从糖酵解到糖酵解的关键代谢转换。肠道形态发生过程中的线粒体呼吸（oxphos）。在正常肠道发育过程中，肠道旋转与肠道延长同时发生，并且较短的肠道长度通常与 IM 相关，这表明肠道伸长机制是 IM 不可或缺的一部分。旋转过程。事实上，细胞分析表明 ATR 扰乱了肠道驱动所需的关键事件延长，包括早期间充质到上皮的转变（MET）和后来的运动核迁移 (IKNM)——最近发现常见的形态发生过程受到细胞代谢状态的影响。总之，这些数据表明，从糖酵解到氧化磷的代谢转变驱动了适当的通过调节肠道期间 MET 和 IKNM 事件的时间和/或定位来进行肠道旋转伸长。该假设将使用创新的代谢组学技术进行测试，以确定：1）如何 ATR 影响肠道形态发生过程中细胞代谢的时空动态，以及 2) 如何影响动态细胞代谢状态影响发育中 MET 和 IKNM 的时间和定位肠。成功完成这些目标将阐明人们对 IM 病因知之甚少的问题，并将代谢改变毒素、疾病和/或妊娠状况在发育中的作用的影响依赖于 MET 和/或 IKNM 介导的形态发生的结构性出生缺陷。