Defining the role of retromer-like in endolysosomal cargo sorting in health and disease.

定义类逆转录酶在健康和疾病中的内溶酶体货物分选中的作用。

基本信息

批准号：
MR/P018807/1
负责人：
Peter Cullen
金额：
$ 235.52万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP018807%2F1
关键词：
Defining role retromer like endolysosomal

项目摘要

All human cells are composed of an outer boundary that is defined by a complex mixture of protein and lipids called the plasma membrane. This encircles a fluid filled 3-dimensional space, termed the cytosol, which contains additional membrane defined compartments each composed of a unique combination of proteins and lipids. For cells to function normally, proteins and lipids must be efficiently transported to the correct organelle within this maze of membranes - organelle being another term for describing a 'membrane defined compartment' that performs a particular cellular function(s). Not surprisingly, if such transport is perturbed, so that the wrong proteins and lipids are delivered to the incorrect organelle, the function of that organelle can be adversely affected leading to de-regulated cell, tissue and organism level physiology. In turn this leads to the development of various diseases. Establishing the mechanisms through which cells achieve regulated protein and lipid transport is therefore a major challenge in cell biology with direct implication for our understanding of human disease.For over ten years our laboratory has focused on describing the mechanistic details that control regulated transport of proteins and lipids with a specific aspect of the cell's membraneous maze termed the endolysosomal network. In particular, we have studied an ancient, highly evolutionary conserved protein complex called retromer. Our research, and that of others, is defining retromer function and in so doing is revealing its importance in a variety of cellular processes that are vital for normal cell function. Furthermore, it has become apparent that defects in retromer underlie a variety of human diseases including age-related neurodegenerative diseases such as Parkinson disease and Alzheimer disease. While the importance of retromer is increasingly recognised, a major unanswered question relates to the mechanism(s) of retromer-independent protein and lipid transport. Addressing this question would constitute a major advance for the field: (i), it is an essential step towards achieving a detailed mechanistic understanding of these processes; (ii), increased mechanistic understanding will provide further insight into de-regulated protein and lipid transport in human disease; and (iii), as evidence continues to define retromer de-regulation in neurodegenerative disease, understanding the integration of retromer-dependent and retromer-independent pathways is likely to provide rationale routes for therapeutic strategies that exploit the flexibility within the endolysosomal network to compensate for retromer dysfunction.In the current programme, we aim to build on our recent identification of a previously unrecognised protein assembly that orchestrates retromer-independent protein and lipid transport within the endolysosomal network - we have termed this 'retromer-like'. From the existing literature there appears to be links between retromer-like de-regulation and neurodegenerative disease, and in preliminary studies we have revealed additional links to hypercholesterolaemia (high blood cholesterol). The study of retromer-like will therefore provide new insight into these, and other, human diseases.In the programme, we describe a holistic approach supported by national and international collaborations, to apply a broad but focused array of cutting-edge techniques to address two inter-related aims:1). The fundamental question of how retromer-like functions as a 'machine' to regulate protein and lipid sorting through the endolysosomal network.2). The application of acquired knowledge to define how retromer-like's activity is required for in vivo cell, tissue and organism-level physiology and how this is de-regulated in human disease.

所有人类细胞都由一个外部边界组成，该外部边界由称为质膜的蛋白质和脂质的复杂混合物定义。它围绕着一个充满液体的三维空间，称为胞质溶胶，其中包含额外的膜限定的隔室，每个隔室由蛋白质和脂质的独特组合组成。为了使细胞正常发挥功能，蛋白质和脂质必须有效地运输到这个迷宫般的膜内正确的细胞器 - 细胞器是描述执行特定细胞功能的“膜限定区室”的另一个术语。毫不奇怪，如果这种运输受到干扰，从而将错误的蛋白质和脂质递送到不正确的细胞器，则该细胞器的功能可能会受到不利影响，导致细胞、组织和生物体水平的生理学失调。反过来，这会导致各种疾病的发生。因此，建立细胞实现蛋白质和脂质转运调节的机制是细胞生物学中的一项重大挑战，对我们对人类疾病的理解有直接影响。十多年来，我们的实验室一直致力于描述控制蛋白质和脂质转运调节的机制细节。脂质具有细胞膜迷宫的特定方面，称为内溶酶体网络。特别是，我们研究了一种古老的、高度进化保守的蛋白质复合物，称为逆转录酶。我们和其他人的研究正在定义逆转录酶的功能，并以此揭示其在对正常细胞功能至关重要的各种细胞过程中的重要性。此外，很明显，逆转录酶的缺陷是多种人类疾病的基础，包括与年龄相关的神经退行性疾病，如帕金森病和阿尔茨海默病。尽管人们越来越认识到逆转录酶的重要性，但一个尚未解答的主要问题与逆转录酶无关的蛋白质和脂质转运的机制有关。解决这个问题将构成该领域的重大进步：（i）这是实现对这些过程的详细机械理解的重要一步； (ii) 增加对机制的了解将进一步深入了解人类疾病中蛋白质和脂质运输的失调； (iii)，随着证据继续定义神经退行性疾病中逆转录酶失调，了解逆转录酶依赖性和逆转录酶独立途径的整合可能为利用内溶酶体网络内的灵活性来补偿的治疗策略提供合理的途径。在当前的项目中，我们的目标是建立在我们最近鉴定的先前未被识别的蛋白质组装的基础上，该蛋白质组装在内溶酶体网络内协调独立于逆转录酶的蛋白质和脂质运输 - 我们称之为“类似逆转录酶”。从现有文献来看，类逆转录酶失调与神经退行性疾病之间似乎存在联系，并且在初步研究中，我们发现了与高胆固醇血症（高血液胆固醇）的其他联系。因此，类逆转录酶的研究将为这些以及其他人类疾病提供新的见解。在该计划中，我们描述了一种由国家和国际合作支持的整体方法，以应用广泛但有针对性的尖端技术来解决两个相互关联的目标：1）。基本问题是类逆转录酶如何作为“机器”通过内溶酶体网络调节蛋白质和脂质分类。2)。应用所获得的知识来定义体内细胞、组织和生物体水平的生理学如何需要类逆转录酶活性，以及这种活性如何在人类疾病中失调。