The Circadian Metabolome and its Interplay with Nutritional Challenges

描述（由申请人提供）：生物钟控制着一系列显著的生理和代谢功能。由于遗传突变和非遗传干扰破坏生物钟导致代谢紊乱，因此必须了解昼夜节律和代谢过程如何在细胞和组织特异性水平上相互作用。昼夜节律基因表达有助于组织特异性代谢稳态是已知的，但代谢物如何发挥这一作用几乎完全未知。因为小的代谢物是核受体的众所周知的配体。其中许多控制细胞的代谢状态，并且也已知在表达中振荡，代谢组在昼夜节律钟维持中的作用对于理解代谢稳态和昼夜节律之间的密切联系是开创性的。这里提出的研究将有助于通过确定昼夜代谢组来填补这一空白，并确定它是如何改变以诱导肥胖的，或者它是否会因肥胖而改变。我们还将把代谢组与昼夜节律转录组联系起来， 确定这两者是否以协调的方式循环。随着越来越多的证据强调生物钟在连接表观遗传控制和细胞代谢中的作用，这项研究对人类生理学和疾病具有深远的影响。

DESCRIPTION (provided by applicant): The circadian clock controls a remarkable array of physiological and metabolic functions. As both genetic mutations and non-genetic interferences that disrupt the circadian clock lead to metabolic disorders, it is essential to understand how circadian rhythms and metabolic processes interact on a cell and tissue-specific level. That circadian gene expression contributes to tissue-specific metabolic homeostasis is known but how metabolites play into this picture is almost completely unknown. As small metabolites are well known ligands of nuclear receptors. many of which control the metabolic state of the cell and are also known to oscillate in expression, the role of the metabolome in circadian clock maintenance is seminal to understanding the intimate links between metabolic homeostasis and circadian rhythms. The research proposed here will help to fill this void by identifying the circadian metabolome and to establish how it changes to induce obesity or whether it changes as a result of obesity. We will also link the metabolome to the circadian transcriptome, which will establish whether these two cycle in a coordinated manner. As accumulating evidence stresses the role of the circadian clock in linking epigenetic control and cellular metabolism, this researc has far-reaching implications for human physiology and disease.