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.

项目摘要/摘要肠道畸形（IM）是一种高度普遍的先天缺陷，可能导致威胁生命需要手术干预和长期补充营养。阿特拉津（ATR），无处不在的除草剂发现电子传输链（ETC）反应在高频下引起IM。初步的数据表明，ATR降低了线粒体呼吸（即氧化磷酸化； Oxphos），并增加发育中的肠道中的糖酵解活性。但是，虽然早期的肠道发育可以固定在糖酵解上一个人，后来的肠发展需要Oxphos。因此，ATR可能会阻止从糖酵解到的关键代谢开关肠形态发生过程中线粒体呼吸（OXPHOS）。在正常的肠发展过程中，肠道旋转随着肠道的延长而同时发生，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不可或缺的旋转过程。实际上，细胞分析表明，驱动肠道所需的ATR Perturbs至关重要的事件延长，包括早期间充质到上皮过渡（MET），以及随后的核核迁移（IKNM） - 最近发现的常见形态发生过程受细胞代谢状态的影响。总之，这些数据表明，从糖酵解到OXPHOS驱动的代谢转换适当通过调节肠道中Met和IKNM事件的定时和/或定位，肠道旋转伸长。该假设将使用创新的代谢组学技术进行检验以确定：1） ATR影响肠形态发生过程中细胞代谢的时空动力学，以及2）动态细胞代谢状态会影响发育中MET和IKNM的时间和定位肠。这些目标的成功完成将阐明IM的理解不足的病因，并将有对改变代谢毒素，疾病和/或妊娠条件在发育中的作用的影响取决于MET和/或IKNM介导的形态发生的结构出生缺陷。