RNA World:科研目的

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RNA World 的科研目的

项目:CRISPR

  • CRISPR 是原核生物免疫防御系统的组成部分,能帮助原核生物抵抗入侵的病毒,可看作是一个简单的微生物免疫系统。

By employing RNA World to systematically screen organisms for the presence of the various types of this defence machinery, we hope to acquire important information on the global distribution and varieties of this system. There is an enormous repertoire of potential applications to the results of such analyses ranging from the improvement of industrially relevant microbial food production to novel ways of coping with multi-drug resistant pathogenic bacteria.

借助 RNA World 平台,可以系统的筛选出具有这种防御机制的各类生物,我们希望能够获知这些生物的种类和它们在全球的分布情况。基于对这些生物分析的结果,从改善工业加工微生物食品到多种抗药性病原菌的新的复制方式研究,都将会有巨大的潜在应用。

References:

  • Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, Romero DA, Horvath P. CRISPR provides acquired resistance against viruses in prokaryotes. Science. 2007 Mar 23;315(5819):1709-12.
  • Wiedenheft B, Zhou K, Jinek M, Coyle SM, Ma W, Doudna JA. Structural basis for DNase activity of a conserved protein implicated in CRISPR-mediated genome defense. Structure. 2009 Jun 10;17(6):904-12.
  • Hale CR, Zhao P, Olson S, Duff MO, Graveley BR, Wells L, Terns RM, Terns MP. RNA-guided RNA cleavage by a CRISPR RNA-Cas protein complex. Cell. 2009 Nov 25;139(5):945-56.
  • Marraffini LA, Sontheimer EJ. CRISPR interference: RNA-directed adaptive immunity in bacteria and archaea. Nat Rev Genet. 2010 Feb 2.



项目:GEMM

  • The GEMM RNA motif is a so-called cis-acting riboswitch designed to detect the second messenger cyclic di-GMP. The bottom line is that GEMM is an upstream terminal part of an mRNA that can bind to this small signal molecule. Upon binding, its structure is modulated such that the downstream part of the mRNA which encodes a protein is affected in such a way that, depending on the type of GEMM motif, the corresponding protein production is either activated or inactivated. Hence, GEMM serves as an RNA-based molecular switch to control protein production.
  • GEMM (Genes for the Environment, for Membranes and for Motility)RNA结构域是一种称为“顺式反应核开关”的,起到检测第二信使环状di-GMP的作用的RNA结构。本质上,GEMM一个mRNA的上游末端的一部分,能够同di-GMP这种小信号分子相结合。结合后,GEMM的结构被修饰,使得下游的编码蛋白的mRNA根据GEMM结构域类型的不同而受到激活或抑制蛋白表达的影响。因此,GEMM是一种基于RNA的控制蛋白合成的分子开关。

The reason for why we are interested in this RNA module is twofold: (1) its switch properties make it very useful for synthetic biology applications and (2) GEMM controls production of proteins that are essential for the capability of certain pathogens to attack human cells. Examples for such pathogens are the cholera-causing bacterium Vibrio cholerae or Bacillus anthracis which is responsible for anthrax.

What RNA World does is a systematical screen of all completely sequenced organisms in order to identify this GEMM motif.

我们对这种RNA调控感兴趣的原因有两个:(1)其分子开关的特性在可以在人工生物合成的应用中起到作用;(2)GEMM控制着对于一些细菌的致病性能力至关重要的蛋白的合成,比如造成霍乱的霍乱弧菌(Vibrio cholera)和引起炭疽热的炭疽杆菌(Bacillus anthracis)RNA World所做的工作就是系统地扫描所有已经完整测序的物种,以鉴定出这个GEMM结构域。

References:

  • Sudarsan N, Lee ER, Weinberg Z, Moy RH, Kim JN, Link KH, Breaker RR. Riboswitches in eubacteria sense the second messenger cyclic di-GMP. Science. 2008 Jul 18;321(5887):411-3.
  • Smith KD, Lipchock SV, Ames TD, Wang J, Breaker RR, Strobel SA. Structural basis of ligand binding by a c-di-GMP riboswitch. Nat Struct Mol Biol. 2009 Dec;16(12):1218-23.

参考文献:

  • Sudarsan N, Lee ER, Weinberg Z, Moy RH, Kim JN, Link KH, Breaker RR. 真细菌中感知第二信使环状di-GMP的核开关. Science. 2008 Jul 18;321(5887):411-3.
  • Smith KD, Lipchock SV, Ames TD, Wang J, Breaker RR, Strobel SA. 同c-di-GMP核开关相结合的配体的结构基础. Nat Struct Mol Biol. 2009 Dec;16(12):1218-23.



项目:6S

  • 6S RNA 是一种长度为200核酸左右的短小非编码RNA,在细菌中广泛存在,并且在一个物种中经常存在多个基因拷贝。6S RNA似乎代表着一种在营养限制的环境下抑制RNA聚合酶的功能调控系统。有意思的是,由于其特殊的结构,这种RNA能够作为RNA的模板,使得细菌的 “持家”RNA聚合酶在营养条件恢复的情况下能够合成miRNA大小的小RNA序列,因此证实了RNA聚合酶既可以用DNA作为模板,也可以用RNA作为模板。


In this project we attempt to chart the presence of this regulatory system in all completely sequenced organisms.

在这个项目中,我们试图在所有已经完整测序的物种中,找到并标记出这种调控系统。

References:

  • Willkomm DK, Hartmann RK. 6S RNA - an ancient regulator of bacterial RNA polymerase rediscovered. Biol Chem. 2005 Dec;386(12):1273-7.
  • Wassarman KM, Saecker RM. Synthesis-mediated release of a small RNA inhibitor of RNA polymerase. Science. 2006 Dec 8;314(5805):1601-3.
  • Gildehaus N, Neusser T, Wurm R, Wagner R. Studies on the function of the riboregulator 6S RNA from E. coli: RNA polymerase binding, inhibition of in vitro transcription and synthesis of RNA-directed de novo transcripts. Nucleic Acids Res. 2007;35(6):1885-96.
  • Wassarman KM. 6S RNA: a regulator of transcription. Mol Microbiol. 2007 Sep;65(6):1425-31.

参考文献

  • Willkomm DK, Hartmann RK. 6S RNA – 一种被重新发现的古老的RNA聚合酶调控因子. Biol Chem. 2005 Dec; 386(12):1273-7.
  • Wassarman KM, Saecker RM. 合成介导释放的RNA聚合酶小RNA抑制因子. Science. 2006 Dec 8;314(5805):1601-3.
  • Gildehaus N, Neusser T, Wurm R, Wagner R. 大肠杆菌核调控因子6S RNA的功能研究:RNA聚合酶结合、体外转录抑制以及RNA为模板的原生RNA合成. Nucleic Acids Res. 2007;35(6):1885-96.
  • Wassarman KM. 6S RNA: 一种转录调控因子. Mol Microbiol. 2007 Sep;65(6):1425-31.



项目:Thermo

  • All organisms examined so far to this respect respond to a sudden decrease in ambient temperature by inducing a specialized genetic program termed the cold shock response (CSR). This cellular stress response is designed to cope with a broad variety of temperature-dependent modulations of molecular structures, transport processes, chemical reactivities, and many more.
  • 在目前已经在这个方面研究过的有机体上讲,有机体会在受到环境温度突然下降的刺激的时候启动一个特殊的基因层面上的程序,称为冷激(冷休克)反应(CSR)。这种细胞的应急反应被设计成应对一系列的温度相关的分子结构调控、分子转运以及化学反应等等。

The goal of this project is to systematically identify non-coding RNAs (ncRNAs) involved in thermoregulation in all organisms whose genomes have been completely sequenced.

该项目的目标就是系统地鉴定非编码 RNA(ncRNAs)在温度调控中的作用,研究的对象是所有已经被完整测定了基因组的物种。

References:

  • Weber MHW, Marahiel MA. Bacterial cold shock responses. Sci Prog. 2003;86(Pt 1-2):9-75.

参考文献:

  • Weber MHW, Marahiel MA. 细菌的冷休克反应. Sci Prog. 2003;86(Pt 1-2):9-75.



项目:Mtb, Myctu, Mycle & Myc

  • Mycobacterium tuberculosis is the the causative agent of tuberculosis (TB) which is a world-wide pandemic that is contagious and spreads through the air. Scaringly, more than two billion people, equal to one third of the world’s total population, are infected with TB bacilli. Even worse, multidrug-resistant TB (MDR-TB) is a form of TB that does not respond to the standard treatments using first-line drugs and is present in virtually all countries surveyed by WHO and its partners. Strikingly, a total of 1.77 million people died from TB in 2007, equal to about 4800 deaths a day which makes TB one of the world's major causes of death.
  • 结核分支杆菌(Mycobacterium tuberculosis)是造成结核病的主要病原体。结核病是一种全球范围内流行的,能够通过空气传播的传染性疾病。令人毛骨悚然的事实是,全世界超过有20亿,约占世界总人口的三分之一的人感染有结核分枝杆菌。更糟的是,多药物抵抗性的结核病菌(MDR-TB)是一种使用一般的一线药物治疗不起任何作用的结核病菌,且根据世界卫生组织(WHO)的调查,这种病菌事实上已经存在于所有该组织及其成员调查过的国家内。2007年,有177万人惨死于结核病,相当于每天致死4800人。这使得结核病已经成为世界上首要的死亡原因之一。

Since it is known that certain non-coding RNAs (ncRNAs) are required to control the ability of many pathogens to infect their hosts, in this project we undertake an exhaustive search to map all ncRNAs known to date in this organism. Moreover, including the leprosy-causing agent Mycobacterium leprae, we extend our bioinformatic analyses to all fully sequenced strains of the genus Mycobacterium and also compare pathogenic versus non-pathogenic strains to possibly identify ncRNA-based differences that might be involved in virulence processes. To validate the biological and medical relevance of our computational investigations, laboratory experiments are performed in cooperation with our research partners in India. It is clear that the potentially possible identification of a ncRNA which is essential for pathogenicity of this organism may represent an excellent novel drug target to battle TB in the future.

由于我们已经知道,特定的非编码RNA(ncRNAs)是很多病原提感染宿主所必须的,在这个项目中,我们试图进行一种地毯式比对搜寻,将该病原的迄今已知的所有ncRNAs都进行定位。此外,我们将我们的生物信息学研究扩展到了所有已经完整测定了基因组的分支杆菌属(Mycobacterium)的其他物种上,比如造成麻风病的麻风杆菌(Mycobacterium leprae)等,将致病的和非致病的品系进行比对,以试图鉴定出ncRNA上的差别,找到与致病性过程相关的ncRNA。为了验证我们计算方法的适用性,我们的研究伙伴同时在印度进行实验室工作(以验证计算的准确性)。显然,如果能够鉴定出在结核杆菌致病性中起关键作用的ncRNA,那么在将来就有可能造就出一种有效的击败结核病的新药

References:

  • Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE 3rd, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998 Jun 11;393(6685):537-44.
  • Camus JC, Pryor MJ, Médigue C, Cole ST. Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv. Microbiology. 2002 Oct;148(Pt 10):2967-73.
  • Terwilliger TC, Park MS, Waldo GS, Berendzen J, Hung LW, Kim CY, Smith CV, Sacchettini JC, Bellinzoni M, Bossi R, De Rossi E, Mattevi A, Milano A, Riccardi G, Rizzi M, Roberts MM, Coker AR, Fossati G, Mascagni P, Coates AR, Wood SP, Goulding CW, Apostol MI, Anderson DH, Gill HS, Eisenberg DS, Taneja B, Mande S, Pohl E, Lamzin V, Tucker P, Wilmanns M, Colovos C, Meyer-Klaucke W, Munro AW, McLean KJ, Marshall KR, Leys D, Yang JK, Yoon HJ, Lee BI, Lee MG, Kwak JE, Han BW, Lee JY, Baek SH, Suh SW, Komen MM, Arcus VL, Baker EN, Lott JS, Jacobs W Jr, Alber T, Rupp B. The TB structural genomics consortium: a resource for Mycobacterium tuberculosis biology. Tuberculosis (Edinb). 2003;83(4):223-49.
  • Chhabria M, Jani M, Patel S. New frontiers in the therapy of tuberculosis: fighting with the global menace. Mini Rev Med Chem. 2009 Apr;9(4):401-30.



项目:sRib

  • “核酶”是一种非编码的RNA,这种分子如同蛋白类的酶一样,能催化化学(生化)反应的进行。典型的例子有:锤头状核酶、HDV(丁型肝炎病毒)核酶、发卡状核酶等等。

In this project we are screening the kingdom of life for the presence of ribozymes. We also include artificially designed ribozymes in order to find out whether natural analogs exist.

在该项目中,我们试图筛选出各种存在的核酶。我们同时包含了人工设计的一些核酶,以便找出是否存在天然的同型物。

References:

  • Tang J, Breaker RR. Structural diversity of self-cleaving ribozymes. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5784-9.
  • Johnston WK, Unrau PJ, Lawrence MS, Glasner ME, Bartel DP. RNA-catalyzed RNA polymerization: accurate and general RNA-templated primer extension. Science. 2001 May 18;292(5520):1319-25.
  • Zaher HS, Unrau PJ. Selection of an improved RNA polymerase ribozyme with superior extension and fidelity. RNA. 2007 Jul;13(7):1017-26.
  • Lincoln TA, Joyce GF. Self-sustained replication of an RNA enzyme. Science. 2009 Feb 27;323(5918):1229-32. Epub 2009 Jan 8.

参考文献:

  • Tang J, Breaker RR.自我剪切的核酶的多样性. Proc Natl Acad Sci U S A. 2000 May 23;97(11):5784-9.
  • Johnston WK, Unrau PJ, Lawrence MS, Glasner ME, Bartel DP. RNA催化的RNA聚合:精确而通用的以RNA为模板的引物延伸. Science. 2001 May 18;292(5520):1319-25.
  • Zaher HS, Unrau PJ. Selection of an improved RNA polymerase ribozyme with superior extension and fidelity. RNA. 2007 Jul;13(7):1017-26.
  • Lincoln TA, Joyce GF. RNA核酶的自主性复制. Science. 2009 Feb 27;323(5918):1229-32. Epub 2009 Jan 8.



项目:tRNA和类tRNA

  • tRNAs are essential components of the cellular protein production machinery but also serve a number of additional functions as e.g. regulating gene expression in conjunction with the T-box element or are utilized as primers for reverse transcription of the HIV genome, a process essential for viral integration into the host genome. Moreover, tRNAs are also required for building the bacterial cell wall and occur in certain lipids making them an extremely versatile molecule family. Interestingly, a number of tRNA-like sequences have been identified in plant virus genomes and appear to be linked to the regulation of viral replication.
  • tRNAs不仅是细胞制造蛋白的机器中的一个重要组件,同时也承担着许多其他的功能,如,与T-box元件进行结合对基因的表达进行调控,或者在HIV基因组进行逆转录以便整合到宿主基因组的过程中扮演引物的作用。此外,tRNAs在构建细胞壁和特定的脂类中也是必不可少的,这使得它们成为一个功能极其多样的分子家族。有趣的是,在一些植物病毒中发现的一些类似于tRNA的序列,似乎和病毒复制的调控有关。

In this project, we aim at compiling a complete survey on the occurrence of tRNAs and tRNA-like sequences hoping to identify even more variety in this fundamental molecule class.

在这个项目中,我们的目标是收集一套完整的关于tRNAs和类tRNAs存在的调查数据,希望鉴定出这类基础性分子类别中更加丰富的多样性。

References:

  • Wegrzyn G, Wegrzyn A. Is tRNA only a translation factor or also a regulator of other processes? J Appl Genet. 2008;49(1):115-22.
  • Dreher TW. Role of tRNA-like structures in controlling plant virus replication. Virus Res. 2009 Feb;139(2):217-29. Epub 2008 Jul 30.
  • Rich A. The era of RNA awakening: structural biology of RNA in the early years. Q Rev Biophys. 2009 May;42(2):117-37. Epub 2009 Jul 29.
  • Pütz J, Giegé R, Florentz C. Diversity and similarity in the tRNA world: overall view and case study on malaria-related tRNAs. FEBS Lett. 2010 Jan 21;584(2):350-8.
  • Francklyn CS, Minajigi A. tRNA as an active chemical scaffold for diverse chemical transformations. FEBS Lett. 2010 Jan 21;584(2):366-75.



参考文献:

  • Wegrzyn G, Wegrzyn A. tRNA仅仅是转录因子,还是其他过程的调控因子?Appl Genet. 2008;49(1):115-22.
  • Dreher TW. 类tRNA结构在控制植物病毒复制中的作用. Virus Res. 2009 Feb;139(2):217-29. Epub 2008 Jul 30.
  • Rich A. RNA觉醒的时代:崛起中的RNA结构生物学. Q Rev Biophys. 2009 May;42(2):117-37. Epub 2009 Jul 29.
  • Pütz J, Giegé R, Florentz C. tRNA世界中的多样性和相似性:概述及以疟疾相关的tRNA为例. FEBS Lett. 2010 Jan 21;584(2):350-8.
  • Francklyn CS, Minajigi A. tRNA: 一种参与多种化学变化的活跃的化学构型. FEBS Lett. 2010 Jan 21;584(2):366-75.

项目:T-box

  • The T-box leader is part of the 5' end of a number of mRNAs and represents an RNA element that serves a regulatory function in controlling protein production by interacting with non-charged tRNAs.
  • T-box是一些信使RNA(mRNA)5’端末端的一部分,表现为一种RNA元件,同未带有氨基酸的tRNA进行结合,从而起到控制蛋白合成的调控作用。

In this project, the RNA World supercomputer is utilized to identify T-box elements throughout the kingdom of life.

在这个项目中,我们使用RNA World超级计算机进行所有物种的T-box元件的鉴定。

References:

  • Grundy FJ, Rollins SM, Henkin TM. Interaction between the acceptor end of tRNA and the T box stimulates antitermination in the Bacillus subtilis tyrS gene: a new role for the discriminator base. J Bacteriol. 1994 Aug;176(15):4518-26.
  • Gerdeman MS, Henkin TM, Hines JV. Solution structure of the Bacillus subtilis T-box antiterminator RNA: seven nucleotide bulge characterized by stacking and flexibility. J Mol Biol. 2003 Feb 7;326(1):189-201.
  • Green NJ, Grundy FJ, Henkin TM. The T box mechanism: tRNA as a regulatory molecule. FEBS Lett. 2010 Jan 21;584(2):318-24.

参考文献:

  • Grundy FJ, Rollins SM, Henkin TM. tRNA受体端同T-box作用引发的枯草芽孢杆菌tyrS基因的抗终止作用:鉴别碱基(注:指tRNA鉴别读码框转运氨基酸)的新的功能. J Bacteriol. 1994 Aug;176(15):4518-26.
  • Gerdeman MS, Henkin TM, Hines JV.解读枯草芽孢杆菌T-box抗终止子的结构:具有堆积性和弹性的长7个核酸的突泡(注:配对的一段RNA上存在的未被配对的几个碱基). J Mol Biol. 2003 Feb 7;326(1):189-201.
  • Green NJ, Grundy FJ, Henkin TM.T-box的功能机制:作为调控分子的tRNA. FEBS Lett. 2010 Jan 21;584(2):318-24.



项目:GA(Genome Annotation)

  • Whenever a new genome sequence is published, its sequence of letters (i.e. the bases of the DNA molecules it contains) is annotated computationally. During this process, all regions are being identified that, based on the standard genetic code and a number of well-known rules, code for proteins. Besides ribosome-related RNAs such as rRNAs and tRNAs and a number of universally occurring non-coding RNAs, the majority of ncRNAs usually escape detection.
  • 当一个新的基因组被测定并公布时,需要使用计算的方法对其序列进行注释。在这个过程中,所有编码蛋白的区域的注释都是基于标准的基因编码,以及一些广为所知的规则来进行的。除了核糖体相关的RNA,如rRNA(核糖体RNA)和tRNA(转运RNA)以及一系列的广泛存在的非编码RNA,众数的非编码 RNA(ncRNA)一般都逃过了检测(,从而未被注释出来)。

In this project, we focus on exclusively filling in the gaps resulting from current protein-focused genome annotation procedures by systematically identifying ncRNAs and by adding our results to those generated by the standard methods.

在这个项目中,我们专注于系统地鉴别ncRNA,以填补当下以蛋白为中心的基因组注释过程所造成的空白区域,并将这些结果添加到以标准方法产生的结果中。