Znhit1在发育信号转导中的调控机制

The goal of project is to study the regulatory mechanisms of Znhit1 in developmental signal transduction pathways. Znhit1 is an evolutionary conserved zinc finger protein. In vitro cell culture experiments suggest that Znhit1 is involved in important biological processes such as cell cycle regulation, but so far it is unknown about the in vivo functions of Znhit1 during development. Using genetic screen in Drosophila, our laboratory at the first time demonstrates that Znhit1 is required for BMP signaling. We have also generated null alleles of Znhit1. Further characterization of Znhit1 indicates that it also involved in Toll signaling pathway. In this proposal, we will use Drosophila as a major model combining mammalian tissue culture system to examine further the mechansims of Znhit1 in regulating BMP, Toll and other developmental signaling pathways. Our ultimate objective is to fully understand the regulatory mechamisms of Znhit1 in development. To achieve this goal, we will utilize various techniques of genetics, cell biology and biochemistry in combination of mass spectrometry method to elucidate the detailed mechanisms. Considering the important roles of BMP and Toll in development and pathology, the accomplishement of this project will deepen our understanding of the mechanisms of developmentally regulated signaling network, and will provide insight into biotherapy of relevant human diseases.

本项目旨在研究Znhit1在发育信号转导中的调控机制。Znhit1蛋白是一个进化上高度保守的锌指蛋白，体外细胞培养实验表明该基因参与细胞周期调控等生物学过程，但迄今为止对Znhit1在体内的功能尚未报道。本实验室利用遗传筛选首次鉴定果蝇中Znhit1参与BMP信号调控，并建立了Znhit1突变体果蝇，进一步研究显示该基因也参与Toll信号转导的调控。本项目将以果蝇为模式动物，结合哺乳动物细胞培养体系，采用遗传学、细胞生物学和生物化学的技术手段，进一步深入研究Znhit1调控BMP、Toll以及其它发育信号通路的分子机制，最终达到对Znhit1调控发育机制的全面了解。鉴于BMP及Toll通路在发育及病理过程中的重要作用，本项目的实施将加深我们对机体发育信号间复杂的调控网络的理解，并将为人类相关疾病的防治提供新的思路。

Znhit1 蛋白是一个进化上高度保守的锌指蛋白，体外细胞培养实验表明该基因参与细胞周期调控等生物学过程，但迄今为止对Znhit1 在体内的功能尚未报道。本项目以果蝇为模式动物，通过Znhit1突变体果蝇，结合哺乳动物细胞培养体系，深入研究了Znhit1 调控BMP、Toll 以及其它发育信号通路的分子机制。首先，Znhit1主要具有协同H2av进行果蝇转录组调控的功能和作用。Znhit1通过控制H2az和H2av的转换，控制Spn100A和Spn43Aa的转录，从而抑制Toll信号通路和免疫应答。另外在成虫盘中的实验显示其能够影响区域细胞的整体泛素化水平，并且在S2细胞中与BMP信号通路转录因子Mad具有相互作用关系。最后，该基因在果蝇肠道系统中对肠道干细胞的功能调控作用也是至关重要的。本项目的结果说明，Znhit1作为从果蝇到人都高度保守的锌指蛋白，通过控制H2az和H2av的转换，在不同的组织和系统中参与不同信号通路的调控，从而发挥多种功能，这有助于我们深刻理解不同组织对不同信号产生特异效应机制，也为最终阐明各种发育信号的调控机制提供理论依据。