The Circadian Metabolome and its Interplay with Nutritional Challenges

描述(申请人提供)：生物钟控制着一系列显著的生理和代谢功能。由于扰乱生物钟的基因突变和非遗传干扰都会导致代谢紊乱，因此了解昼夜节律和代谢过程如何在细胞和组织特定的水平上相互作用是至关重要的。昼夜节律的基因表达有助于组织特定的代谢动态平衡是已知的，但代谢物如何在这一图景中发挥作用几乎完全未知。因为小的代谢物是众所周知的核受体的配体。其中许多基因控制细胞的代谢状态，也被认为在表达上振荡，代谢组在生物钟维持中的作用对于理解代谢动态平衡和昼夜节律之间的密切联系具有重要意义。这里提出的研究将有助于通过识别昼夜节律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，这将 确定这两个周期是否协调一致。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新陈代谢中的作用，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.