Molecular and metabolic pathways controlling developmental timing. TempoReg

控制发育时间的分子和代谢途径。

• 批准号: EP/X021521/1
• 负责人: Teresa Rayon
• 金额: $ 164.72万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX021521%2F1
• 关键词: Molecular; metabolic; pathways; controlling; developmental

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.

生物学上的一个长期以来的问题是发育时机如何在细胞水平上运作。尽管哺乳动物物种之间的发展计划相似，但发展程序功能的速度（tempo）是特定于物种的。此外，某些物种可以响应不良的营养条件（肿瘤）而停止长时间的发育。可以在体外概括物种之间的时间差异，并且物种之间的比较干细胞模型在体外概括了，率先鉴定了节奏机制。我的工作确定拆除蛋白质的速率与发育节奏相对应，蛋白质降解速率降低与速度较慢有关。但是，调节蛋白质更新的后果仍有待测试，并且在发育节奏的上游机制仍有待确定。了解节奏如何调节将有助于我们了解发展速度的变化如何导致大小的变化以及定时是进化变化的来源。Temporeg旨在对分子和代谢途径进行整体理解，从而通过与全基因组的动态蛋白质组学，代谢和转录学辅助的探索来控制节奏的分子和代谢途径，从而控制节奏，从而控制节奏，从而控制节奏。调节发展速度。具体而言，Temporeg将解决以下问题：（1）蛋白质转换在发育节奏中的作用是什么？ （2）速度如何通过代谢机制控制？（3）我们可以调节物种内的发育节奏吗？以及对一个基本问题的启示，对分子，细胞，有机体和进化量表的含义具有含义，该项目也具有广泛的实际应用。改变发育过程的速度可能会减少从用于研究或用于研究或治疗应用的胚胎干细胞中生产人类特异性细胞类型的时间尺度。

项目成果

Delay of human early development via in vitro diapause

• DOI: 10.1101/2023.05.29.541316
• 发表时间: 2023-05
• 期刊: bioRxiv
• 作者: Dhanur P. Iyer;V. V. D. Weijden-V.;Heidar Heidari Khoei;A. McCarthy;Teresa Rayon;Claire S. Simon;I. Dunkel;Sissy E. Wamaitha;K. Elder;Phil Snell;L. Christie;Edda G. Schulz;K. Niakan;N. Rivron;Aydan Bulut-Karslioğlu