Identification and characterization of circular RNAs in differentiation and human disease

环状RNA在分化和人类疾病中的鉴定和表征

基本信息

项目摘要

Recent advances in RNA biology have drawn attention to an unexplored class of non-coding RNAs that correspond to circular isoforms of spliced transcripts. Animal cells express thousands of circRNAs at levels comparable to mRNAs, often in a tissue- or developmental stage-specific way. CircRNAs are naturally exonuclease-resistant, and thus highly stable - inside and outside of cells. Emerging evidence suggests a role for circRNAs in post-transcriptional regulation; however, their relevance to human development and disease is unknown. We will test the hypothesis that circRNAs may be suitable biomarkers for differentiation or disease. We will identify circRNAs in human blood, saliva, urine, and mesenchymal stem cells (MSC) from healthy donors and patients. We will investigate MSC before and after differentiation into fat (metabolic syndrome), vascular smooth muscle (hypertension), bone or cartilage (skeletal phenotypes). We will also investigate circRNAs in infectious disease and cancer.Specifically, we have established collaborations to investigate colon and pancreatic cancers (Charité Comprehensive Cancer Center, Berlin), Burkitt lymphoma and immune cells infected with EBV, Kaposi sarcoma-associated HHV-8, and HHV-7 (Pfeffer laboratory, U. Strasbourg) or HIV and M. tuberculosis (Goldfeld laboratory, Harvard Medical School). This joint proposal from the Rajewsky laboratory (MDC Berlin-Buch) and the Luft laboratory (Charité - Medical University Berlin, Humboldt U.) has five aims. Aim 1: To establish a standardized protocol for purification and deep sequencing of ribosomal RNA-depleted transcriptomes and circRNAs from different tissue and sample types. Aim 2: To develop a standardized computational pipeline that can map, analyze and annotate circRNA sequence data in a high-throughput manner. Aim 3: To identify and characterize circRNAs from primary human MSC and MSC-derived, differentiated cell types in order to gain insight into the role of circRNAs during tissue development and perpetuation. Aim 4: To identify and investigate circRNAs from clinically relevant human samples, including virally infected tissues and tumors, in order to elucidate the potential of circRNAs as biomarkers for diagnosis and therapeutical interventions. Aim 5: To make all protocols, computational codes and sequencing data publicly available via doRiNA, a curated database freely accessible at dorina.mdc-berlin.de. We expect that this project will 1) provide - as a community resource - protocols, computational code, as well as comprehensive ribosomal RNA-depleted transcriptome data from different tissues, virally infected cells and clinical samples; 2) identify and annotate corresponding circRNA data sets; 3) specifically identify human or virus-derived circRNAs associated with differentiation and disease states; 4) prioritize circRNAs for future functional or translational follow-up studies (which are themselves beyond the scope of this proposal).
RNA生物学的最新进展引起了人们对一类未被探索的非编码RNA的关注,这些RNA对应于剪接转录物的环状同种型。动物细胞表达成千上万的circRNA,其水平与mRNA相当,通常以组织或发育阶段特异性的方式。CircRNA是天然的核酸外切酶抗性,因此在细胞内外高度稳定。新出现的证据表明circRNA在转录后调节中的作用;然而,它们与人类发育和疾病的相关性尚不清楚。我们将检验circRNA可能是分化或疾病的合适生物标志物的假设。我们将鉴定人类血液、唾液、尿液和来自健康供体和患者的间充质干细胞(MSC)中的circRNA。我们将研究分化为脂肪(代谢综合征)、血管平滑肌(高血压)、骨或软骨(骨骼表型)之前和之后的MSC。我们还将研究感染性疾病和癌症中的circRNA。具体而言,我们已经建立了合作研究结肠癌和胰腺癌(Charité Comprehensive Cancer Center,柏林),伯基特淋巴瘤和EB病毒感染的免疫细胞,卡波西肉瘤相关的HHV-8和HHV-7(Pfeffer实验室,U.斯特拉斯堡)或HIV和M.结核病(Goldfeld实验室,哈佛医学院)。这一联合提案来自Raublsky实验室(MDC Berlin-Buch)和Luft实验室(Charité - Medical University柏林,洪堡大学)。有五个目标。目标1:建立一个标准化的方案,用于纯化和深度测序来自不同组织和样本类型的核糖体RNA缺失转录组和circRNA。目标2:开发一个标准化的计算管道,可以以高通量的方式映射,分析和注释circRNA序列数据。目标3:鉴定和表征来自原代人MSC和MSC衍生的分化细胞类型的circRNA,以深入了解circRNA在组织发育和延续过程中的作用。目标4:鉴定和研究临床相关人类样本(包括病毒感染组织和肿瘤)中的circRNA,以阐明circRNA作为诊断和治疗干预生物标志物的潜力。目标5:通过doRiNA公开所有方案、计算代码和测序数据,doRiNA是一个可在dorina.mdc-berlin.de免费访问的策展数据库。我们期望该项目将1)提供-作为社区资源-来自不同组织、病毒感染细胞和临床样品的方案、计算代码以及全面的核糖体RNA耗尽的转录组数据; 2)鉴定和注释相应的circRNA数据集; 3)特异性鉴定与分化和疾病状态相关的人类或病毒衍生的circRNA; 4)优先考虑circRNA用于未来的功能或翻译后续研究(其本身超出了本提案的范围)。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function
  • DOI:
    10.1126/science.aam8526
  • 发表时间:
    2017-09-22
  • 期刊:
  • 影响因子:
    56.9
  • 作者:
    Piwecka, Monika;Glazar, Petar;Rajewsky, Nikolaus
  • 通讯作者:
    Rajewsky, Nikolaus
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Professor Dr. Friedrich C. Luft其他文献

Professor Dr. Friedrich C. Luft的其他文献

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{{ truncateString('Professor Dr. Friedrich C. Luft', 18)}}的其他基金

Normobaric hypoxia training compared to ambient training on the course of the metabolic syndrom: influence on muscle function and structure
常压低氧训练与环境训练对代谢综合征病程的比较:对肌肉功能和结构的影响
  • 批准号:
    214218192
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Zur Rolle der löslichen Epoxidhydrolase bei der Hypertonieentstehung
可溶性环氧化物水解酶在高血压发生中的作用
  • 批准号:
    5397113
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Molecular genetics of the eclampsia/preeclampsia syndrome
子痫/先兆子痫综合征的分子遗传学
  • 批准号:
    5179984
  • 财政年份:
    1999
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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