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Defining the molecular structure-function relationships of extracellular vesicles from dying cells.

定义死亡细胞的细胞外囊泡的分子结构-功能关系。

基本信息

批准号：
BB/M006298/1
负责人：
Andrew Devitt
金额：
$ 56.66万
依托单位：
Aston University
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM006298%2F1
关键词：
Defining molecular structure function relationships

项目摘要

Damaged, infected, aged or unwanted cells in the body die via a highly controlled process known as 'apoptosis'. Apoptosis is important in a range of normal tissue functions, embryonic development, removing infected cells, controlling immune responses to infection, and in a range of age-associated disease conditions including inflammatory diseases, cancer, neurodegeneration and cardiovascular disease. At sites where levels of death are high, professional 'scavenger' cells (phagocytes known as macrophages) are recruited. These phagocytes are attracted to 'find me' signals released from dying cells and then phagocyte receptors bind 'eat me' signals on the dying cell surface. It is crucially important for phagocytes to bury dying cells quickly because otherwise leakage of dead cell contents can occur. This in turn leads to catastrophic consequences of inflammation (e.g. in atherosclerosis) and autoimmune disease (e.g. systemic lupus erythematosus). We have made a significant impact on the field of cell death by defining an 'eat me' signal (a protein called ICAM-3) and an important receptor that mediates eating (CD14). However, whilst much is known of molecules that mediate phagocytic removal of dying cells, very little is known of the identity and function of the 'find me' signals. We are one of a small group of scientists addressing the nature of these signals.When dying, cells release small membrane 'bags' ('apoptotic cell-derived extracellular vesicles' or 'acdEV') that bleb and pinch off from the surface of dying cells. The full function of these acdEV is unknown and little is known of their composition. We have shown recently that dying white blood cells release ICAM-3 on acdEV to create an attractive 'path' that leads phagocytes to the site of cell death where they can clear the cell corpses in a safe and controlled manner. However, little is known of other acdEV functions. Our work raised important questions for the field of cell death. (1) What is the composition of acdEV? (2) How does this composition relate to function? In this programme of work we will address these fundamental gaps in our knowledge. We will analyse acdEV release from different types of dying cells (immune and non-immune system cells) and will define the composition and function of these particles. We will undertake a detailed analysis of (A) the PROTEINS contained within and on the surface of these acdEV to define the protein constitution of the acdEV; (B) the LIPID constituents of the acdEV; and (C) the small nucleic acid molecules ('microRNA') contained within the acdEV. We will focus on individual acdEV components by increasing or decreasing their molecular presence and assess their functional ability to interact with and modulate the immune system in a range of assays both in vitro and in vivo.This work will, for the first time, detail the molecular composition and link this to function of acdEV thereby answering important questions and advancing the field significantly. It will define, at a molecular level, how dying cells communicate with other cells to ensure that they are removed rapidly without leading to inflammation. This is important because defective clearance of dying cells leads to disease. Thus exploitation of our work will target those conditions where inefficient dead cell clearance results in damaging inflammatory responses (e.g. in atherosclerosis).

体内受损、感染、老化或不需要的细胞会通过高度受控的过程（称为“细胞凋亡”）死亡。细胞凋亡对于一系列正常组织功能、胚胎发育、清除受感染的细胞、控制对感染的免疫反应以及一系列与年龄相关的疾病（包括炎症性疾病、癌症、神经退行性疾病和心血管疾病）非常重要。在死亡水平较高的地方，专业的“清道夫”细胞（称为巨噬细胞的吞噬细胞）被招募。这些吞噬细胞被垂死细胞释放的“找到我”信号所吸引，然后吞噬细胞受体结合垂死细胞表面的“吃我”信号。对于吞噬细胞来说，快速埋葬垂死细胞至关重要，否则可能会发生死细胞内容物的泄漏。这反过来又导致炎症（例如动脉粥样硬化）和自身免疫性疾病（例如系统性红斑狼疮）的灾难性后果。通过定义“吃我”信号（一种称为 ICAM-3 的蛋白质）和介导进食的重要受体 (CD14)，我们对细胞死亡领域产生了重大影响。然而，虽然人们对介导吞噬细胞清除垂死细胞的分子了解甚多，但对“找到我”信号的身份和功能却知之甚少。我们是研究这些信号本质的一小群科学家之一。细胞死亡时，会释放小膜“袋”（“凋亡细胞衍生的细胞外囊泡”或“acdEV”），这些膜“袋”会从垂死细胞的表面起泡并夹断。这些 acdEV 的全部功能尚不清楚，对其组成也知之甚少。我们最近表明，垂死的白细胞在acdEV上释放ICAM-3，创建一条有吸引力的“路径”，引导吞噬细胞到达细胞死亡部位，在那里它们可以以安全和受控的方式清除细胞尸体。然而，人们对 acdEV 的其他功能知之甚少。我们的工作对细胞死亡领域提出了重要问题。（1）acdEV的构成是什么？ (2) 该组合物与功能有何关系？在本工作计划中，我们将解决我们知识中的这些基本差距。我们将分析不同类型的垂死细胞（免疫和非免疫系统细胞）释放的 acdEV，并定义这些颗粒的组成和功能。我们将对（A）这些acdEV内部和表面所含的蛋白质进行详细分析，以确定acdEV的蛋白质构成； (B) acdEV 的 LIPID 成分； (C) acdEV 中包含的小核酸分子（“microRNA”）。我们将通过增加或减少其分子存在来关注单个acdEV成分，并评估其在体外和体内一系列测定中与免疫系统相互作用和调节免疫系统的功能能力。这项工作将首次详细介绍分子组成并将其与acdEV的功能联系起来，从而回答重要问题并显着推进该领域的发展。它将在分子水平上定义垂死细胞如何与其他细胞沟通，以确保它们被快速清除而不会导致炎症。这很重要，因为死亡细胞的清除缺陷会导致疾病。因此，我们的工作将针对那些死细胞清除效率低下导致破坏性炎症反应的情况（例如动脉粥样硬化）。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Communicating with the dead: lipids, lipid mediators and extracellular vesicles.

DOI：
10.1042/bst20160477
发表时间：
2018-05
期刊：
Biochemical Society transactions
影响因子：
3.9
作者：
A. Devitt;H. Griffiths;I. Milic
通讯作者：
A. Devitt;H. Griffiths;I. Milic

Phospholipid oxidation and carotenoid supplementation in Alzheimer's disease patients.

DOI：
10.1016/j.freeradbiomed.2017.03.008
发表时间：
2017-07
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Ademowo OS;Dias HKI;Milic I;Devitt A;Moran R;Mulcahy R;Howard AN;Nolan JM;Griffiths HR
通讯作者：
Griffiths HR

Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils.

DOI：
10.1038/cddis.2016.481
发表时间：
2017-03-02
期刊：
Cell death & disease
影响因子：
9
作者：
Castro SA;Collighan R;Lambert PA;Dias IH;Chauhan P;Bland CE;Milic I;Milward MR;Cooper PR;Devitt A
通讯作者：
Devitt A

Emerging roles for AQP in mammalian extracellular vesicles.