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Investigating the mechanisms of phosphatidylcholine sensing

研究磷脂酰胆碱传感机制

基本信息

批准号：
BB/T005610/1
负责人：
Symeon Siniossoglou
金额：
$ 53万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FT005610%2F1
关键词：
Investigating mechanisms phosphatidylcholine sensing

项目摘要

Biological membranes are essential for all aspects of life; they separate the interior of cells from their environment; they organize the intracellular space into several compartments, or organelles, each with its own specific role; and they also function as platforms onto which complex chemical reactions take place. The basic building blocks of membranes are lipids. Therefore, it is critical that cells produce lipids at the right time and place. The amount and type of membrane lipids must be carefully controlled to match the specific requirements of each cell: for example, rapidly proliferating cells or cells expanding their intracellular organelles require more lipid synthesis to support the growth of the corresponding membranes. In this project we will investigate how cells monitor and adjust the levels of phosphatidylcholine (PC), the most abundant lipid in eukaryotic membranes.The enzyme that controls the rate of PC production is called CCTa. Because PC is a cylindrical lipid, its depletion disrupts proper lipid packing within the membrane; this is sensed by CCTa, which is then activated to correct the defect. We recently found that this process takes place inside the nucleus of many different eukaryotic cells: when inactive, CCTa is intranuclear, while when cells need to make more PC, the enzyme associates with the inner side of the nuclear membrane, which separates the nucleus from the cytoplasm. This finding is surprising given that lipid synthesis is mostly a cytoplasmic process. In the proposed work, we will determine how CCTa associates with the inner nuclear membrane, why this process is restricted within the nucleus and how it is coordinated with the final step of PC synthesis which takes place in the cytoplasm.Our recent work shows that the sensing of PC is highly conserved from simple unicellular organisms to humans. Therefore, we will carry out the initial discovery phase of our research in budding yeast as a model organism that provides rapid insights; in a second phase we will determine how these outcomes apply in human cells. We believe that this work will contribute to the understanding of a fundamental step in lipid metabolism and could guide future therapeutic approaches against lipid metabolic and visual disorders, which are caused by PC deficiency.

生物膜对生命的各个方面都至关重要；它们将细胞内部与环境分离；它们将细胞内的空间组织成若干个室或细胞器，每个室或细胞器都有其特定的作用；它们还可以作为复杂化学反应发生的平台。细胞膜的基本组成部分是脂质。因此，细胞在正确的时间和地点产生脂质是至关重要的。必须仔细控制膜脂的数量和类型，以匹配每个细胞的特定需求：例如，快速增殖的细胞或细胞内细胞器的扩张需要更多的脂质合成来支持相应膜的生长。在这个项目中，我们将研究细胞如何监测和调节磷脂酰胆碱（PC）的水平，磷脂酰胆碱是真核生物膜中最丰富的脂质。控制PC生成速率的酶被称为CCTa。由于PC是一种圆柱形脂质，它的耗尽破坏了膜内适当的脂质堆积；这是由CCTa感应到的，然后激活它来纠正缺陷。我们最近发现，这一过程发生在许多不同真核细胞的细胞核内：当失活时，CCTa在核内，而当细胞需要制造更多的PC时，该酶与核膜的内侧结合，将细胞核与细胞质分开。考虑到脂质合成主要是细胞质过程，这一发现令人惊讶。在这项工作中，我们将确定CCTa如何与核膜结合，为什么这一过程被限制在细胞核内，以及它如何与发生在细胞质中的PC合成的最后一步协调。我们最近的工作表明，PC的感知是高度保守的，从简单的单细胞生物到人类。因此，我们将对出芽酵母进行初步发现阶段的研究，作为一种模式生物，提供快速的见解；在第二阶段，我们将确定这些结果如何应用于人类细胞。我们相信这项工作将有助于理解脂质代谢的一个基本步骤，并可以指导未来治疗由PC缺乏引起的脂质代谢和视觉障碍的方法。