Unveiling novel functions of peroxisomal lipid-binding proteins in interorganellar cooperation and regulation of lipid metabolism

揭示过氧化物酶体脂质结合蛋白在细胞器间合作和脂质代谢调节中的新功能

• 批准号: BB/N01541X/1
• 负责人: Michael Schrader
• 金额: $ 53.86万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN01541X%2F1
• 关键词: Unveiling; novel; functions; peroxisomal; lipid

One of the hallmarks of eukaryotic cells is the presence of membrane-bound compartments (organelles), which create different optimised environments to promote various metabolic reactions required to sustain life. For the entire cell to function as a unit, coordination and cooperation between specialized organelles must take place. Peroxisomes are multifunctional subcellular organelles that are essential for human health and development. Peroxisome dysfunctions contribute to several inherited organelle disorders with diverse pathology which are often difficult to diagnose and to treat. Peroxisomes play pivotal cooperative roles in the metabolism of cellular lipids and reactive oxygen species (ROS) and influence neuronal development and ageing processes. Lipids have many important functions in the cell and organism, for example as energy source, signalling molecules or components of cellular membranes. The disturbance of cellular lipid balance and altered cellular energy regulation is a risk factor for the initiation and progression of common, age-related diseases such as diabetes, cardiovascular disease, neurodegeneration, cancer and obesity. Peroxisome dysfunctions have been linked to degenerative disorders. Moreover, important roles for peroxisomes in signalling and the fine-tuning of cellular processes are emerging, which integrate them in a complex network of interacting cellular compartments. Despite this importance for human health and disease, our knowledge on how peroxisomes interact and communicate with other organelles and contribute to the regulation of cellular lipid homeostasis that impact on normal physiology and disease processes is scarce. The overall aim of this project is to acquire novel insights into peroxisome-organelle association, lipid metabolism and transfer processes in normal and disease conditions.In this project we will (1) reveal the molecular mechanism underlying peroxisome-organelle association and identify and characterise specific proteins involved in this interaction to understand the organelle interplay and its impact on disease pathology; we will (2) develop approaches to investigate the function of these proteins in peroxisomal membrane dynamics and (3) in the specific degradation of peroxisomes; both processes have an impact on human development and healthy ageing. Finally, we will (4) assess the role of novel peroxisomal membrane proteins in the transport and degradation of fatty acids to understand the pathophysiology of a novel peroxisome-related disorder. In summary, in this interdisciplinary project we will combine unique complementary expertise in organelle-biology and organelle-based disorders with novel tools and models in human cell biology. We will apply molecular cell biology, biochemical approaches, proteomics and cutting edge imaging techniques to elucidate how novel peroxisomal membrane proteins contribute to organelle communication, the regulation of lipid metabolism and the development of organelle-based disorders. Specifically, this research project will improve our understanding of novel lipid-binding proteins and their impact on healthy ageing and common, degenerative disorders. We will generate new tools and cellular models for assessing organelle interplay and the role of novel membrane proteins in health and disease. Understanding of the link between organelle interplay, lipid metabolism and disease pathology will be of significant biological and medical importance. It may contribute to the discovery of new targets to modulate the regulation of lipid metabolism and cellular energy regulation in healthy ageing and age-related disorders.

真核细胞的特征之一是存在膜结合的隔室(细胞器)，它们创造不同的优化环境来促进维持生命所需的各种代谢反应。为了使整个细胞作为一个单位发挥作用，必须在专门的细胞器之间进行协调和合作。过氧化物体是一种多功能的亚细胞细胞器，对人类的健康和发育至关重要。过氧化物酶体功能障碍导致几种遗传性细胞器疾病，这些细胞器疾病具有不同的病理，通常难以诊断和治疗。过氧酶体在细胞脂质和活性氧(ROS)的代谢中起着关键的协同作用，并影响神经元的发育和衰老过程。脂类在细胞和生物体中具有许多重要的功能，例如作为能源、信号分子或细胞膜的成分。细胞脂平衡失调和细胞能量调节改变是糖尿病、心血管疾病、神经变性、癌症和肥胖症等常见年龄相关疾病发生和发展的危险因素。过氧化酶体功能障碍与退行性疾病有关。此外，过氧化体在信号传递和细胞过程的微调中的重要作用正在显现，这将它们整合到一个相互作用的细胞间隔的复杂网络中。尽管这对人类健康和疾病很重要，但我们对过氧化体如何与其他细胞器相互作用和通信，并有助于调节影响正常生理和疾病过程的细胞脂稳态的了解很少。这个项目的总体目标是获得对正常和疾病条件下的过氧化物体-细胞器结合、脂质代谢和转移过程的新见解。在这个项目中，我们将(1)揭示过氧化物体-细胞器结合的分子机制，并识别和表征参与这种相互作用的特定蛋白质，以了解细胞器的相互作用及其对疾病病理学的影响；(2)开发方法来研究这些蛋白质在过氧化体膜动力学中的功能和(3)在过氧酶体的特定降解中；这两个过程都对人类发育和健康衰老产生影响。最后，我们将(4)评估新的过氧酶体膜蛋白在脂肪酸运输和降解中的作用，以了解一种新的过氧酶体相关疾病的病理生理学。总而言之，在这个跨学科的项目中，我们将把细胞器生物学和基于细胞器的疾病方面独特的互补专业知识与人类细胞生物学的新工具和模型结合起来。我们将应用分子细胞生物学、生化方法、蛋白质组学和前沿成像技术来阐明新的过氧化体膜蛋白如何在细胞器通讯、脂代谢调节和细胞器疾病的发展中发挥作用。具体地说，这项研究项目将提高我们对新的脂结合蛋白及其对健康老龄化和常见的退行性疾病的影响的理解。我们将产生新的工具和细胞模型来评估细胞器的相互作用和新的膜蛋白在健康和疾病中的作用。了解细胞器相互作用、脂质代谢和疾病病理之间的联系将具有重要的生物学和医学意义。它可能有助于发现新的靶点，以调节健康衰老和老年相关疾病中脂代谢和细胞能量调节的调节。

项目成果

Supplemental Material1 - Supplemental material for Fluorescent Tools to Analyze Peroxisome-Endoplasmic Reticulum Interactions in Mammalian Cells

补充材料1 - 用于分析哺乳动物细胞中过氧化物酶体-内质网相互作用的荧光工具的补充材料

• DOI: 10.25384/sage.8184455
• 发表时间: 2019
• 作者: Bishop A

A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes.

• DOI: 10.1111/tra.12549
• 发表时间: 2018-03
• 期刊: Traffic (Copenhagen, Denmark)
• 作者: Castro IG;Richards DM;Metz J;Costello JL;Passmore JB;Schrader TA;Gouveia A;Ribeiro D;Schrader M
• 通讯作者: Schrader M

Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations.

• DOI: 10.1080/15384101.2017.1314422
• 发表时间: 2017-06-03
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: Costello JL;Castro IG;Schrader TA;Islinger M;Schrader M
• 通讯作者: Schrader M

ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER.

• DOI: 10.1083/jcb.201607055
• 发表时间: 2017-02
• 期刊: The Journal of cell biology
• 作者: Costello JL;Castro IG;Hacker C;Schrader TA;Metz J;Zeuschner D;Azadi AS;Godinho LF;Costina V;Findeisen P;Manner A;Islinger M;Schrader M
• 通讯作者: Schrader M

Fluorescent tools to analyse peroxisome-ER interactions in mammalian cells.

• DOI: 10.1177/2515256419848641
• 发表时间: 2019-06-05
• 期刊: Contact (Thousand Oaks (Ventura County, Calif.))
• 作者: Bishop, Alexa;Kamoshita, Maki;Schrader, Michael
• 通讯作者: Schrader, Michael