权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Active Extracellular Vesicles - defining a novel, extracellular metabolic compartment and its role in the control of inflammation.

活性细胞外囊泡 - 定义了一种新型的细胞外代谢区室及其在控制炎症中的作用。

基本信息

批准号：
BB/S00324X/1
负责人：
Andrew Devitt
金额：
$ 99.13万
依托单位：
Aston University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS00324X%2F1
关键词：
Active Extracellular Vesicles defining novel

项目摘要

Inflammation is a normal defence mechanism used by the immune system to help protect from infection and to repair damage caused by trauma. However, the benefits of inflammation are only realised when the response is turned off and the infected or traumatised tissue is returned to normal. This process is known as 'resolution' and relies on immune cells (that have done their protective job) being removed. To allow their removal, these unwanted cells die and, as they do so, they release small membrane bags (called extracellular vesicles: EV). We have shown that these EV are key to attracting 'undertaker' cells ('macrophages') that remove the dying cells by eating them and, crucially, they produce additional signals that drive the tissue to repair.Relatively little is known of how these EV function. We have identified a molecule that promotes recruitment of macrophages but the manner in which these EV promote 'repair' responses in macrophages remains unknown. Now, our preliminary work has shown that these EV carry a family of active enzymes which will help to produce small lipid molecules that may control inflammation and repair responses. The work proposed here will define the action of these active enzymes that are delivered from dying cells to macrophages in EV. As such, these 'active' EV represent a novel extracellular metabolically-active compartment capable of transmitting inflammation-controlling signals to surrounding cells such as macrophages.Why is this important? A failure to control inflammatory responses can lead to chronic inflammation and many of the inflammatory diseases associated with ageing. So, by understanding the mechanisms of communication between cells promoting inflammation, and those cells promoting resolution and repair, we will have a clearer insight to possible therapeutic approaches for diseases that are driven by inflammation (e.g. cardiovascular disease, cancer, neurodegeneration). Furthermore, we will study EV from a range of other cells that are known to help promote repair. For example, a type of stem cell, an 'MSC', has held great promise for regenerative medicine but recently the EV released from these cells have been proposed to be active to stimulate a 'repair environment'. Consequently, we will study in detail the inflammation-controlling metabolic activity of EV from MSC. This raises the possibility that we may be able to define the crucial factors required for EV repair activity, opening up novel stem cell-based or cell-free therapies for regenerative medicine. In order to test our core hypothesis, we will analyse, from a range of dying and viable cells, EV composition for the presence of enzymes, their substrates and their products. We will test the EVs' ability to promote repair in vitro and in vivo and we will inhibit the key enzymes to assess the essential nature of this activity. Furthermore, we will seek to 'tune' or refine cell culture conditions to maximise EV production and function.This work will, for the first time, detail an inflammation-controlling, metabolically-active extracellular compartment. It will define, at a molecular level, how dying cells communicate with other cells to ensure inflammation is controlled. This is important because ineffective control of inflammation leads to disease. Thus, exploitation of our work will target those conditions where inflammation helps drive disease and will enable novel strategies to promote self-repair.

炎症是免疫系统的一种正常防御机制，用于帮助保护免受感染和修复创伤造成的损伤。然而，只有当这种反应被关闭，感染或创伤的组织恢复正常时，炎症的好处才会实现。这个过程被称为“解决”，依赖于免疫细胞（已经完成了它们的保护工作）被移除。为了让它们被清除，这些不需要的细胞会死亡，并在此过程中释放出小的膜袋（称为细胞外囊泡：EV）。我们已经证明，这些EV是吸引“承受者”细胞（“巨噬细胞”）的关键，巨噬细胞通过吞噬死亡细胞来清除死亡细胞，更重要的是，它们产生额外的信号，推动组织修复。相对而言，人们对这些EV的功能知之甚少。我们已经确定了一种促进巨噬细胞募集的分子，但这些EV促进巨噬细胞“修复”反应的方式仍然未知。现在，我们的初步工作已经表明，这些EV携带一个活性酶家族，它将有助于产生可能控制炎症和修复反应的小脂质分子。这里提出的工作将定义这些活性酶的作用，这些活性酶从死亡细胞递送到EV中的巨噬细胞。因此，这些“活性”EV代表了一种新的细胞外代谢活性区室，能够向周围细胞（如巨噬细胞）传递炎症控制信号。为什么这很重要？不能控制炎症反应会导致慢性炎症和许多与衰老相关的炎症性疾病。因此，通过了解促进炎症的细胞与促进消退和修复的细胞之间的交流机制，我们将更清楚地了解由炎症驱动的疾病（例如心血管疾病，癌症，神经退行性疾病）的可能治疗方法。此外，我们将从一系列已知有助于促进修复的其他细胞中研究EV。例如，一种干细胞，“MSC”，在再生医学中有着巨大的前景，但最近，从这些细胞中释放的EV被认为是活跃的，可以刺激“修复环境”。因此，我们将详细研究来自MSC的EV的炎症控制代谢活性。这增加了一种可能性，我们可能能够定义EV修复活性所需的关键因素，为再生医学开辟新的基于干细胞或无细胞的疗法。为了验证我们的核心假设，我们将从一系列死亡细胞和活细胞中分析酶、底物和产物的EV组成。我们将在体外和体内测试ev促进修复的能力，我们将抑制关键酶来评估这种活性的本质。此外，我们将寻求“调整”或完善细胞培养条件，以最大限度地提高电动汽车的产量和功能。这项工作将首次详细描述炎症控制、代谢活跃的细胞外隔室。它将在分子水平上定义垂死细胞如何与其他细胞交流以确保炎症得到控制。这一点很重要，因为对炎症控制不力会导致疾病。因此，利用我们的工作将针对那些炎症帮助驱动疾病的情况，并将启用促进自我修复的新策略。