Molecular and metabolic pathways controlling developmental timing. TempoReg

生物学中一个长期存在的问题是，发育时间如何在细胞水平上发挥作用。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(节奏)是因物种而异的。此外，一些物种可以在很长一段时间内停止发育，以响应不利的营养条件(滞育)。物种之间细胞固有的时间差异可以在体外概括，物种之间的比较干细胞模型开创了鉴定TEMPO机制的先河。我的研究发现，蛋白质分解的速度与发育节奏相对应，而蛋白质降解率的降低与较慢的节奏相关。然而，调节蛋白质周转的后果仍有待测试，发育节奏上游的机制仍有待确定。了解Tempo是如何调节的将有助于我们理解发育速度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的蛋白质组、代谢和转录测量与药理学和遗传扰动相结合，对控制Tempo的分子和代谢途径有一个整体的理解，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)蛋白质周转在发育节奏中的作用是什么？(2)节奏是如何由代谢机制控制的？以及(3)我们能否在一个物种内调节发育节奏？除了揭示一个涉及分子、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用于研究或临床治疗应用的胚胎干细胞生产人类特定细胞类型的时间。

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.