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

该项目旨在描述细胞命运调控的新机制，并描绘潜在的分子事件。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，这一发现彻底改变了再生医学。然而，我们缺乏合理的方法来提高重编程效率。了解调节多能性建立的信号转导机制有望提供干预措施，提高重编程效率，并允许对再生医学进行越来越具体的干预。宿主实验室开创了干细胞生物学中肽基精氨酸脱亚胺酶（PADI）的研究，表明染色质修饰剂PADI 4调节细胞重编程和胚胎发育中多能性的建立。该项目将研究瓜氨酸蛋白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变。我将联合收割机结合我的研究背景与世界一流的专业知识，目前在主机实验室和更广泛的研究所，以解决上述问题，使用细胞生物学，细胞信号和遗传方法以及成像和单细胞转录组学的组合。我将使用类器官培养和体内模型评估我在组织再生方面的发现的生理相关性。这个项目有可能改变我们对重编程过程的理解，并确定促进组织再生的方法，同时为我提供出色的培训，让我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.