Molecular and metabolic pathways controlling developmental timing. TempoReg

生物学中一个长期存在的问题是发育时间在细胞水平上如何运作。尽管哺乳动物物种之间的发育程序相似，但发育程序发挥作用的速度（克里思）是物种特异性的。此外，一些物种可以停止发育的时间延长，以应对不利的营养条件（滞育）。细胞内在的差异，物种之间的时间可以概括在体外，和比较干细胞模型物种之间已经率先识别的克里思机制。我的工作确定了蛋白质分解的速率与发育克里思相对应，蛋白质降解速率的降低与较慢的克里思有关。然而，调节蛋白质周转的后果仍有待测试，发育克里思的上游机制仍有待确定。了解克里思是如何调节的将有助于我们理解发育节奏的变化如何导致大小的变化，以及为什么时间是进化变化的来源。TempoReg旨在通过将全基因组动态蛋白质组学，代谢和转录组学测量与药理学和遗传学扰动相结合，最终目标是确定调节发育速度的机制。具体来说，TempoReg将解决以下问题：（1）蛋白质周转在发育克里思中的作用是什么？(2)新陈代谢机制是如何控制克里思的？以及（3）我们能否调节物种内部的发育克里思？除了阐明一个涉及分子、细胞、生物和进化尺度的基本问题外，该项目还具有广泛的实际应用。改变发育过程的速度可能会缩短从胚胎干细胞生产人类特定细胞类型的时间，这些细胞类型用于临床研究或治疗应用。

A long-held question in biology is how developmental timing operates at the cellular level. Despite the similarities in the developmental programs between mammalian species, the pace (tempo) at which the developmental programs function is species-specific. Further, some species can halt development for extended periods of time in response to adverse nutrient conditions (diapause).Cell-intrinsic differences in timing between species can be recapitulated in vitro, and comparative stem cell models between species have pioneered the identification of tempo mechanisms. My work identified that the rate at which proteins are dismantled corresponds to developmental tempo, with reduced protein degradation rates associated with slower tempo. However, the consequences of modulating protein turnover remain to be tested, and the mechanisms upstream of developmental tempo remain to be identified. Understanding how tempo is modulated will help us understand how changes in the pace of development may lead to changes of size and why timing is a source of evolutionary change.TempoReg aims to develop a holistic understanding of the molecular and metabolic pathways that control tempo by combining genome-wide dynamic proteomic, metabolic and transcriptomic measurements with pharmacological and genetic perturbations, with the ultimate goal of identifying mechanisms to modulate developmental pace. Specifically, TempoReg will address the following questions: (1) what is the role of protein turnover in developmental tempo? (2) how is tempo controlled by metabolic mechanisms?, and (3) can we modulate developmental tempo within a species?As well as shedding light on a fundamental question with implications across molecular, cell, organismal, and evolutionary scales, this project also has broad practical applications. Changing the pace of developmental processes may reduce the timescales for the production of human specific cell types from embryonic stem cells employed for research or for therapeutic applications in the clinic.