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.

大脑的正确功能需要各种细胞类型之间的复杂，快速，有效的细胞间通信。神经元和神经胶质细胞都可以作为细胞间通信的药物产生细胞外囊泡（EV）。电动汽车是通过多种途径产生的异质膜结合室，导致不同的类型和货物。它们与生理和病理间的细胞间通信过程有关，因为它们可以通过血脑屏障转移核酸，蛋白质和脂质以及与疾病相关的分子。最近的研究表明，它们作为生物标志物的潜力，因为在血液，尿液和脑脊液等生物流体中发现了神经元衍生的EV。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主要作用，它是免疫细胞调节剂，并且存在于EV中。此外，DJ-1中的突变引起常染色体隐性PD和DJ-1对PD发病机理的贡献的分子机制仍然不清楚。该项目的目的是表征和了解EVS和DJ-1在生理和病理界面间的作用沟通。我们将通过回答以下问题来实现这一目标：EV种群在没有DJ-1的情况下如何变化？DJ-1货物对受体细胞有什么影响？我们将采用控制或DJ-1基因敲除SH-SY5Y细胞，以及野生型，PD病因和工程的DJ-1突变体来确定EVS局部DJ-1在由健康和帕金森氏症细胞模型中的细胞间通信中的作用神经毒素或 - 突触核蛋白原纤维治疗。通过流式细胞仪，RNASEQ和蛋白质组学的研究，我们的结果将阐明DJ-1货物在细胞间通信中的作用，并为将来研究EV在神经变性中的作用铺平道路。