Defining the Commander endosomal cargo sorting pathway in health and disease.

定义健康和疾病中的 Commander 内体货物分选途径。

• 批准号: MR/Y01183X/1
• 负责人: Peter Cullen
• 金额: $ 317.55万
• 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: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY01183X%2F1
• 关键词: Defining; Commander; endosomal; cargo; sorting

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 twenty 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. Indeed, small and large Pharma now consider Retromer a druggable target for these diseases.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 breakthrough in defining the structure of a multi-protein assembly called Commander, and its function in orchestrating Retromer-independent protein and lipid transport within the endosomal network. Commander de-regulation is causative for X-linked intellectual disability and Ritscher-Schinzel syndrome, a severe developmental disease that affects skeletal development, brain function, and the cardiovascular system. The study of Commander 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 mechanistic question of how Commander functions to organize and regulate protein and lipid sorting through the endosomal network.2). Apply acquired knowledge to establish how the Commander pathway contributes to 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。二十多年来，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Retromer。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，Retromer 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。事实上，小型和大型制药公司现在都认为Retromer是这些疾病的药物靶标。虽然Retromer的重要性越来越被人们所认识，但一个尚未解答的主要问题涉及Retromer独立蛋白和脂质转运的机制。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Retromer失调，了解Retromer依赖性和Retromer非依赖性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。逆转录酶功能障碍。在当前的项目中，我们的目标是在定义称为 Commander 的多蛋白组装结构的最新突破的基础上，及其在内体网络内协调逆转录酶独立的蛋白质和脂质运输中的功能。指挥官放松管制是导致 X 连锁智力障碍和 Ritscher-Schinzel 综合征的原因，Ritscher-Schinzel 综合征是一种严重的发育疾病，影响骨骼发育、大脑功能和心血管系统。因此，Commander 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矛盾的问题相关目标：1）。 Commander 如何通过内体网络组织和调节蛋白质和脂质分选的基本机制问题。2)。应用所获得的知识来确定 Commander 通路如何对细胞、组织和生物体水平的生理学做出贡献，以及它如何在人类疾病中解除管制。