Metabolism and Malrotation

新陈代谢和旋转不良

• 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
• 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

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/摘要 肠旋转不良（IM）是一种非常普遍的出生缺陷，可导致危及生命的条件 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 干扰电子传递链（ETC）反应，被发现会导致IM在高频率。初步 数据显示ATR降低线粒体呼吸（即，氧化磷酸化（oxidative phosphorylation; oxphos） 在发育中的肠中的糖酵解活性。然而，虽然早期肠道发育可以依靠糖酵解生存， 单独，以后的肠道发育需要oxphos;因此，ATR可能会阻止关键的代谢转换，从糖酵解到 线粒体呼吸（oxphos）在肠形态发生。 在正常的肠道发育过程中，肠道旋转与肠道延长同时发生， 较短的肠长度通常与IM相关，这表明肠延长机制是IM不可或缺的。 旋转过程事实上，细胞分析表明，ATR干扰了肠道驱动所需的关键事件， 延长，包括早期间充质-上皮转化（MET）和后来的细胞核迁移 （IKNM）-最近发现的常见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oxphos的代谢转换驱动了适当的 通过调节肠旋转期间MET和IKNM事件的时间和/或定位来调节肠旋转 伸长率这一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影响肠形态发生过程中细胞代谢的时空动力学，以及2）如何 动态细胞代谢状态影响MET和IKNM在发育中的时间和定位。 肠子这些目标的成功实现将阐明尚不清楚的IM病因， 代谢改变毒素、疾病和/或妊娠条件在发育中的作用的意义 结构性出生缺陷依赖于MET和/或IKNM介导的形态发生。