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

Extracellular vesicle RNA as systemic modulators of the tumor microenvironment in B cell lymphoma

细胞外囊泡 RNA 作为 B 细胞淋巴瘤肿瘤微环境的系统调节剂

基本信息

批准号：
345462466
负责人：
Dr. Florian Kuchenbauer
金额：
--
依托单位：
BC Cancer Research Centre
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/345462466?language=en
关键词：
Extracellular vesicle RNA systemic modulators

项目摘要

Extracellular vesicles (EVs) are important mediators of intercellular communication and are involved in many physiological processes. They are present in almost any fluid compartment of our bodies and can be detected even at distant sites of their cell of origin. Within the last decade, their critical involvement in cancer development, progression and dissemination has become more and more obvious. EVs consist of a lipid bilayer membrane displaying cell surface proteins of their cell of origin and contain mainly protein and RNA molecules. It is now clear that EVs can interact with cells via their surface molecules and can transfer their content to target cells. The transferred material, e.g. proteins, messengerRNAs or microRNAs, was shown to be active in recipient cells, leading to changes in their phenotypes. Under physiological conditions, EVs act as mediators of immune responses, and there are indications that tumor-derived EVs contribute to disease-associated inflammation and immune suppression.Tumor cell-derived EVs have so far been mainly studied in solid cancers, and there is only little data on EVs produced by malignant cells in hematological diseases. Therefore, the aim of our proposed project is an extensive analysis of EVs, with a focus on exosomes, derived from malignant cells of chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and diffuse large B cell lymphoma (DLBCL). The study includes i) comparative proteome and RNA analyses of exosomes, with a focus on Y RNAs and microRNAs and their sorting mechanisms; ii) the identification of target cells within the hematopoietic microenvironment that take up tumor-derived exosomes in vitro and in mouse models; iii) a characterization of downstream changes within the transcriptome, secretome and signaling capacities of target cells, focusing hereby on inflammatory responses that are mediated by toll-like receptors; as well as iv) investigations to evaluate the impact of exosomes on B cell lymphoma development in suitable mouse models. Finally, we will v) investigate in a translational approach the potential of exosomes as biomarkers and as therapeutic target in preclinical studies in mice.

细胞外小泡是细胞间通讯的重要介质，参与许多生理过程。它们几乎存在于我们身体的任何液体隔室中，甚至可以在其起源细胞的远处检测到。在过去的十年中，它们在癌症的发生、发展和传播中的重要作用变得越来越明显。EV由展示其来源细胞的细胞表面蛋白的脂质双层膜组成，并且主要含有蛋白质和RNA分子。现在很清楚，EV可以通过其表面分子与细胞相互作用，并可以将其内容物转移到靶细胞。转移的物质，例如蛋白质，信使RNA或microRNA，在受体细胞中显示出活性，导致其表型的变化。在生理条件下，EVs是免疫应答的介质，肿瘤源性EVs可导致疾病相关炎症和免疫抑制。肿瘤细胞源性EVs的研究主要集中在实体瘤中，而恶性肿瘤细胞产生的EVs在血液系统疾病中的研究较少。因此，我们提出的项目的目的是对EV进行广泛的分析，重点是来源于慢性淋巴细胞白血病（CLL）、多发性骨髓瘤（MM）和弥漫性大B细胞淋巴瘤（DLBCL）的恶性细胞的外来体。该研究包括i）外来体的比较蛋白质组和RNA分析，重点是Y RNA和microRNA及其分选机制; ii）在体外和小鼠模型中识别造血微环境中摄取肿瘤来源的外来体的靶细胞; iii）表征靶细胞的转录组、分泌组和信号传导能力内的下游变化，由此集中于由Toll样受体介导的炎症反应;以及iv）研究以评价外来体对合适小鼠模型中B细胞淋巴瘤发展的影响。最后，我们将V）以转化方法研究外泌体作为生物标志物和作为小鼠临床前研究中的治疗靶标的潜力。