PADIngton - The role of protein citrullination in the regulation of cell fate

该项目旨在描述一种新的调控细胞命运的机制，并描述潜在的分子事件。体细胞可以被重新编程为多能状态，并被指示分化为各种细胞类型，这一发现使再生医学发生了革命性的变化。然而，我们缺乏提高重新编程效率的合理方法。了解调节多能性建立的信号转导机制有望提供干预措施，提高重新编程的效率，并允许对再生药物进行越来越特异的干预。东道主实验室开创了干细胞生物学中的多肽精氨酸脱亚氨酶(PADI)酶的研究，表明染色质修饰物PADI4调节细胞重新编程和胚胎发育中多能性的建立。这个项目将研究蛋白质瓜氨酸化如何允许细胞信号输入的整合，以及这如何通过调节染色质状态和基因表达来影响细胞身份转换。我将把我的研究背景与东道主实验室和更广泛的研究所现有的世界级专业知识结合起来，结合细胞生物学、细胞信号和遗传学方法以及成像和单细胞转录学来解决上述问题。我将使用器官培养和活体模型来评估我在组织再生方面的发现的生理学相关性。这个项目有可能改变我们对重新编程过程的理解，并确定促进组织再生的方法，同时为我提供出色的培训，使我能够成长为一名独立的科学家。

This project aims to characterize a novel mechanism in the regulation of cell fate and delineate the underlying molecular events. The discovery that somatic cells can be reprogrammed to a pluripotent state and instructed to differentiate into various cell types has revolutionized regenerative medicine. However, we lack rational approaches to enhance reprogramming efficiency. Understanding the signal transduction mechanisms that regulate the establishment of pluripotency promises to offer interventions that will increase reprogramming efficiency and allow for increasingly specific intervention towards regenerative medicine.The host lab has pioneered the study of peptidylarginine deiminase (PADI) enzymes in stem cell biology, showing that the chromatin modifier PADI4 regulates the establishment of pluripotency in cell reprogramming and embryo development. This project will investigate how protein citrullination allows the integration of cell signalling inputs and how this impacts cell identity transitions through the modulation of chromatin state and gene expression. I will combine my research background with the world-class expertise present in the host lab and wider institute to address the above questions, using a combination of cell biological, cell signalling and genetic approaches as well as imaging and single-cell transcriptomics. I will assess the physiological relevance of my findings in tissue regeneration using organoid cultures and in vivo models. This project has the potential to transform our understanding of the reprogramming process and identify approaches to promote tissue regeneration while providing me with excellent training and allowing me to grow as an independent scientist.