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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.

项目总结/文摘