去泛素化酶OTUB1在肺发育过程中的功能及分子机制研究

OTUB1 is a deubiquitinating enzyme of the OTU subfamily and is reported to be involved in multiple biological processes such as immune regulation, DNA damage repair, tumor progression and development. However, most of the current research on OTUB1 is based on molecular and cellular studies, little is known about its physiological function. So, we established a complete knockout mouse model of OTUB1 gene to explore the physiological function of OTUB1. To our surprise, OTUB1 knockout mice died of lung dysplasia soon after birth, moreover, loss of OTUB1 in the developing lung affects many key signal pathways involved in lung development, such as mTORC1. Although we are beginning to understand some of the molecular and cellular mechanisms that underlie critical processes of lung development, there is still a lack of systematic and in-depth understanding of the regulation mechanism involves the precise temporal and spatial coordination. The function of ubiquitination in lung development also needs to be clarified. Based on the above background and early experimental results, we plan to conduct systematic research in molecular, cell and mouse overall levels. We will confirm what abnormal with the developing lung by OTUB1 knockout, screen and identify the direct target molecules of OTUB1 and study the regulation mechanisms of target molecular by OTUB1 in the lung development, clarify the regulation mechanism of the target molecules on lung development, and then elucidate the function and molecular mechanisms of OTUB1 in regulation of lung development. This study aims to uncover the function and molecular mechanisms of OTUB1 in lung development, and to deepen the understanding of the mechanism of lung development.

OTUB1是OTU亚家族的去泛素化酶，被报道可以参与免疫调节、DNA损伤修复、肿瘤发生发展等多个生物学过程。但这些研究大都是基于分子和细胞水平的体外研究，对其生理功能认识仍然不足，因此，我们建立了OTUB1基因敲除小鼠模型，发现OTUB1基因敲除小鼠在出生后很快死于肺发育异常，且OTUB1敲除影响了肺组织中的mTORC1等。尽管近年来人们对肺发育的机制有了一定的了解，但仍缺乏系统而深入的认识，泛素化在肺发育中的功能也不清楚。基于以上背景及前期实验结果，本项目拟从分子、细胞和小鼠等多个层面开展研究，确认OTUB1敲除引起何种肺发育异常，筛选和鉴定OTUB1在肺发育中直接调控的靶分子并明确OTUB1对靶分子的调控机制，研究靶分子对肺发育的调控机理，进而阐明 OTUB1在肺发育调控中的功能和分子机制。本研究旨在揭示OTUB1在肺发育过程中的功能和分子机制，加深对肺发育机理的认识。

OTUB1是OTU家族的去泛素化酶，被报道可以参与免疫调节、DNA损伤修复、肿瘤发生发展等多个生物学过程。但这些研究大都是基于分子和细胞水平的体外研究，对其生理功能认识仍然不足。尽管近年来人们对肺发育的机制有了一定的了解，但仍缺乏系统而深入的认识，泛素化在肺发育中的功能也不清楚。.在本项目中，我们建立了OTUB1基因敲除小鼠模型，发现OTUB1基因敲除小鼠在出生后很快死于肺发育异常，进一步的研究发现OTUB1敲除小鼠在囊状肺阶段出现肺发育异常，具体为1型肺泡细胞、分泌细胞和弹性纤维发育异常。通过分子和细胞水平的研究，我们发现OTUB1敲除小鼠胚肺中Erk/MAPK和PI3K/AKT信号通路异常，进一步的研究表明OTUB1与肺发育过程中的关键分子FGFR2存在相互作用，并且OTUB1通过去除FGFR2的多聚泛素化修饰正调控 FGFR2 的蛋白稳定性。.本项目从分子、细胞、组织和小鼠整体水平等多个层面开展研究，确认了OTUB1敲除引起何种肺发育异常，筛选和鉴定到了OTUB1在肺发育中直接调控的靶分子FGFR2并明确了OTUB1对靶分子的调控机制，进而阐明了OTUB1在肺发育调控中的功能和分子机制。本研究揭示了OTUB1在肺发育过程中的功能和分子机制，加深了我们对肺发育机理的认识。