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Characterisation of the PI3P-dependent signalling network responsible for nutrient sensing and autophagy

负责营养传感和自噬的 PI3P 依赖性信号网络的表征

基本信息

批准号：
BB/H000631/1
负责人：
Nicholas Ktistakis
金额：
$ 55.24万
依托单位：
Babraham Institute
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2009
资助国家：
英国
起止时间：
2009 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FH000631%2F1
关键词：
Characterisation PI3P dependent signalling network

项目摘要

One of the most important requirements for healthy cellular growth is the ability to sense and respond to extracellular nutrients. When nutrient supply is plentiful, cells need only to fine tune their anabolic and catabolic rates so that their energy requirements match the available resources. When nutrients become limiting or are completely unavailable, a much stronger course of action is required to allow the cells to survive. During such times of nutrient withdrawal, the cells respond by initiating autophagy, a degradative pathway that allows the breakdown of intracellular proteins into amino acids that can be used subsequently for new protein synthesis or energy generation. An important question in autophagy concerns the mechanisms by which cells sense their extracellular nutrient content. Recent work from many groups has indicated that a small lipid molecule termed phosphatidylinositol 3 phosphate (PI3P) is an important signal for nutrient sensing. Our own work also indicates that autophagy is induced partially as a result of the formation of PI3P in specialised membrane compartments called omegasomes. Therefore, the mechanisms and signals that generate PI3P early during autophagy are likely to provide important information on the control of autophagy by nutrient sensing. The aim of this grant is to identify all human genes that are involved in this pathway. We plan to systematically silence all known human genes and then look at the effect that this will have in formation of PI3P during autophagy. By identifying all such genes we will be able to construct a wiring diagram of the cellular pathways that are implicated in nutrient sensing and respond during nutrient limitation by the induction of autophagy.

健康细胞生长最重要的要求之一是感知和响应细胞外营养物质的能力。当营养供应充足时，细胞只需微调其合成代谢和分解代谢速率，使其能量需求与可用资源相匹配。当营养物质变得有限或完全无法获得时，需要采取更强有力的措施才能使细胞生存。在营养缺乏的时期，细胞通过启动自噬来做出反应，自噬是一种降解途径，可以将细胞内蛋白质分解成氨基酸，随后可用于新的蛋白质合成或能量产生。自噬中的一个重要问题涉及细胞感知细胞外营养成分的机制。许多小组最近的工作表明，一种称为磷脂酰肌醇 3 磷酸 (PI3P) 的小脂质分子是营养传感的重要信号。我们自己的工作还表明，自噬的部分诱导是由于 PI3P 在称为 omegasome 的特殊膜区室中形成。因此，自噬早期产生 PI3P 的机制和信号可能为通过营养传感控制自噬提供重要信息。这笔赠款的目的是确定参与该途径的所有人类基因。我们计划系统地沉默所有已知的人类基因，然后观察这对自噬过程中 PI3P 形成的影响。通过识别所有这些基因，我们将能够构建与营养感应有关的细胞通路的接线图，并在营养限制期间通过诱导自噬做出反应。