Metabolism and Malrotation

项目摘要/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 扰乱电子传输链(ETC)反应的物质被发现在高频下引起IM。初步 数据显示，ATR降低线粒体呼吸(即氧化磷酸化；OXPHOS)并增加 发育中的肠道中的糖酵解活动。然而，虽然早期肠道发育可以依靠糖酵解来维持 单独来说，后来的肠道发育需要OXPHOS；因此，ATR可能会阻止从糖酵解到 肠道形态发生中的线粒体呼吸(OXPHOS)。 在正常的肠道发育过程中，肠道旋转与肠道延长同时发生， 较短的肠道长度通常与IM有关，这表明肠道伸长机制是IM不可或缺的 轮换过程。事实上，细胞分析表明，ATR干扰了驱动肠道所需的关键事件 延长，包括早期间充质到上皮的转变(MET)，以及后来的动间核迁移 (IKNM)--最近发现受细胞代谢状态影响的常见形态发生过程。 总而言之，这些数据表明，从糖酵解到OXPHOS的代谢转换是正确的 通过调节肠道中MET和IKNM事件的时间和/或定位来实现肠道旋转 伸长率。这一假设将使用创新的代谢组学技术进行验证，以确定：1)如何 ATR在肠道形态发生过程中影响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在发育过程中的时间和定位 肠子。这些目标的成功实现将阐明IM鲜为人知的病因，并将具有 代谢改变的毒素、疾病和/或妊娠条件在发育中的作用 依赖于MET和/或IKNM介导的形态发生的结构性出生缺陷。

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.