The role of microRNAs in cell:cell communication

microRNA 在细胞间通讯中的作用

• 批准号: BB/H005498/1
• 负责人: David Simpson
• 金额: $ 46.67万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH005498%2F1
• 关键词: role; microRNAs; cell; communication

The project investigates a novel form of communication between cells involving the transfer of small regulatory molecules called 'microRNAs' in small sacs or 'microvesicles'. Many cells generate microvesicles from their cell membranes, enclosing contents from inside the cell. The released microvesicles are carried in the blood, for example, until they contact another cell. They can then interact with the surface of the second cell or actually be taken up and release their contents inside. It has been shown that microvesicles convey 'instructions' telling the recipient cell to, for example, divide or form new blood vessels. Whilst microvesicles are ubiquitous in lower organisms, in vertebrates they have been isolated primarily from blood and other body fluids. It may be that routine passage of microvesicles from cell to cell within tissues has simply not been observed due to the difficulties of detection. If this is the case, they are a hugely underestimated form of communication. One of the classes of molecule carried by microvesicles is microRNA. Over the last few years these small RNAs have been shown to play an indispensable role in regulating gene expression and to be essential for normal development. Each of the ~500 microRNAs present in vertebrates targets several hundred messenger RNA molecules (mRNAs). MicroRNAs therefore have the capacity to 'fine tune' global gene expression patterns. The first objective of the project is to demonstrate that microRNAs carried by microvesicles can alter gene expression in their target cells. This has never been reported and would show that it is feasible for cells to communicate between one another using this mechanism. The second objective is to measure the extent and significance of this form of communication in biological systems. We have chosen to concentrate on a critical physiological process called angiogenesis, whereby new blood vessels are formed from pre-existing vessels. Angiogenesis relies on cell-cell communication and can be readily studied in the laboratory setting. A new technique which can simultaneously measure millions of RNA molecules will be used to investigate whether the microRNAs carried in microvesicles are affecting the expression of genes in the endothelial cells as they form new blood vessels. The main expected outcome of this project is knowledge of whether gene expression can be modulated by microRNAs carried by microvesicles and if this is an important mechanism. The several reports of microRNAs in microvesicles appear to represent a general phenomenon because we have replicated this finding in multiple cell types. Given the known and potentially widespread existence of microvesicles, microRNA transfer could be a significant novel form of inter-cellular communication. If this proves to be the case the beneficiaries of the project would be all those who are working in the field of cellular communication, for example during development. This knowledge could lead to better understanding of certain disease processes. This mechanism is amenable to manipulation and could therefore provide a novel approach for intervention in disease and industrial processes.

该项目研究了一种新型的通信形式，涉及小囊或“微覆盖”中称为“ microRNA”的小调节分子的转移。许多细胞从其细胞膜产生微泡，从细胞内部包围含量。例如，释放的微囊泡在血液中携带，直到它们接触另一个细胞为止。然后，它们可以与第二个单元的表面相互作用，或者实际占用并在其中释放其内容物。已经表明，微囊泡传达“指示”，告诉​​受体细胞，例如分裂或形成新的血管。尽管微囊泡在较低的生物体中无处不在，但在脊椎动物中，它们主要是从血液和其他体液中分离出来的。由于检测的困难，可能没有观察到微囊泡从组织内部的细胞到细胞的常规通过。如果是这种情况，它们是一种被低估的交流形式。通过微泡携带的分子之一是microRNA。在过去的几年中，这些小型RNA在调节基因表达中起着必不可少的作用，对于正常发育至关重要。脊椎动物中存在的约500个microRNA中的每一个都靶向数百个Messenger RNA分子（mRNA）。因此，microRNA具有“微调”全局基因表达模式的能力。该项目的第一个目的是证明微泡中携带的microRNA可以改变其靶细胞中的基因表达。这从未得到过报道，并且会表明，使用这种机制相互通信是可行的。第二个目标是衡量生物系统中这种通信形式的程度和意义。我们选择集中于一种称为血管生成的关键生理过程，从而由先前存在的血管形成新的血管。血管生成依赖于细胞 - 细胞通信，并且可以在实验室环境中容易研究。一种可以同时测量数百万个RNA分子的新技术将用于研究微囊泡中携带的microRNA是否会影响内皮细胞中基因的表达，因为它们形成了新的血管。该项目的主要预期结果是了解是否可以通过微覆载体携带的microRNA调节基因表达，以及这是否是重要的机制。微泡中microRNA的几个报告似乎代表了一种普遍现象，因为我们已经在多种细胞类型中复制了这一发现。鉴于已知且可能广泛存在微泡，MicroRNA转移可能是一种重要的细胞间通信形式。如果事实证明是这样的，那么该项目的受益人将是所有在蜂窝通信领域（例如在开发过程中）的人。这些知识可能会更好地理解某些疾病过程。这种机制可以操纵，因此可以为干预疾病和工业过程提供一种新颖的方法。

项目成果

Preferential export of specific microRNAs and their isomiRs in extracellular vesicles

细胞外囊泡中特定 microRNA 及其 isomiR 的优先输出

• 发表时间: 2014
• 作者: Brown, ED

Distinctive profile of IsomiR expression and novel microRNAs in rat heart left ventricle.

• DOI: 10.1371/journal.pone.0065809
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: McGahon MK;Yarham JM;Daly A;Guduric-Fuchs J;Ferguson LJ;Simpson DA;Collins A
• 通讯作者: Collins A

A novel dual-fluorescence strategy for functionally validating microRNA targets in 3' untranslated regions: regulation of the inward rectifier potassium channel K(ir)2.1 by miR-212.

• DOI: 10.1042/bj20120578
• 发表时间: 2012-11-15
• 期刊: The Biochemical journal
• 作者: Goldoni D;Yarham JM;McGahon MK;O'Connor A;Guduric-Fuchs J;Edgar K;McDonald DM;Simpson DA;Collins A
• 通讯作者: Collins A

Manipulation of the MicroRNA Content of Endothelial Progenitor Cell-derived Extracellular Vesicles

内皮祖细胞来源的细胞外囊泡 MicroRNA 含量的调控

• 发表时间: 2013
• 作者: Simpson D

Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types.

• DOI: 10.1186/1471-2164-13-357
• 发表时间: 2012-08-01
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Guduric-Fuchs J;O'Connor A;Camp B;O'Neill CL;Medina RJ;Simpson DA
• 通讯作者: Simpson DA