Role of extracellular vesicle and DJ-1 in intercellular communication

细胞外囊泡和 DJ-1 在细胞间通讯中的作用

• 批准号: 2431581
• 金额: --
• 依托单位: Aston University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2431581
• 关键词: Role; extracellular; vesicle; DJ; intercellular

Correct function of the brain requires complex, rapid, and efficient intercellular communication between varied cell types. Both neuronal and glial cells can produce extracellular vesicles (EVs) as agents of intercellular communication. EVs are heterogenous membrane-bound compartments produced through multiple pathways, resulting in different types and cargo. They are implicated in both physiological and pathological intercellular communication processes, as they can transfer nucleic acids, proteins, and lipids as well as disease-related molecules through the blood-brain barrier. Recent studies have shown their potential as biomarkers, as neuronal derived EVs were identified in biofluids such as blood, urine and cerebrospinal fluid. Within this context, DJ-1 is a particularly interesting protein: it plays a major role in oxidative stress protection, it acts as immune cell modulator and it is present in EVs. Furthermore, mutations in DJ-1 cause autosomal recessive PD and the molecular mechanisms underlying DJ-1 contribution to PD pathogenesis are still unclear.The aim of this project is to characterise and understand the role of EVs and DJ-1 in physiological and pathological intercellular communication. We will achieve this goal by answering the following questions: how does EV population change in absence of DJ-1 and what is the effect of DJ-1 cargo on recipient cells? We will employ control or DJ-1 knockout SH-SY5Y cells, as well as wild-type, PD causative and engineered DJ-1 mutants to determine the role of EVs localised DJ-1 in intercellular communication in healthy and parkinsonian cell models induced by neurotoxin or -synuclein fibril treatment. Through study by flow cytometry, RNAseq, and proteomics our results will clarify the role of DJ-1 cargo in intercellular communication and pave the way for future studies on EVs role in neurodegeneration.

大脑的正常功能需要不同细胞类型之间复杂、快速和有效的细胞间通讯。神经元和神经胶质细胞都可以产生细胞外囊泡（EV）作为细胞间通讯的媒介。EV是通过多种途径产生的异质性膜结合区室，导致不同的类型和货物。它们涉及生理和病理细胞间通讯过程，因为它们可以通过血脑屏障转移核酸，蛋白质和脂质以及疾病相关分子。最近的研究已经显示了它们作为生物标志物的潜力，因为神经元衍生的EV在生物流体如血液、尿液和脑脊液中被鉴定。在这种情况下，DJ-1是一种特别有趣的蛋白质：它在氧化应激保护中起着重要作用，它作为免疫细胞调节剂存在于EV中。此外，DJ-1基因突变导致常染色体隐性遗传PD，DJ-1参与PD发病的分子机制尚不清楚，本项目的目的是了解EV和DJ-1在生理和病理细胞间通讯中的作用。我们将通过回答以下问题来实现这一目标：在没有DJ-1的情况下EV群体如何变化以及DJ-1货物对受体细胞的影响是什么？我们将采用对照或DJ-1敲除SH-SY 5 Y细胞，以及野生型、PD致病性和工程化DJ-1突变体，以确定EV定位的DJ-1在由神经毒素或β-突触核蛋白原纤维处理诱导的健康和帕金森病细胞模型中的细胞间通讯中的作用。通过流式细胞术，RNAseq和蛋白质组学的研究，我们的结果将阐明DJ-1货物在细胞间通讯中的作用，并为未来研究EV在神经变性中的作用铺平道路。