Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices

修饰核酸结构以探究响应性纳米器件的生化过程和设计原理

基本信息

  • 批准号:
    RGPIN-2017-06683
  • 负责人:
  • 金额:
    $ 3.28万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2022
  • 资助国家:
    加拿大
  • 起止时间:
    2022-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are the central molecules of life. The discovery of the double helix structure of DNA, described by Watson and Crick over 60 years ago, continues to lead to numerous advances in biology and medicine. More recently, this elegant structure and the nature of its specific interactions have inspired scientists and engineers to investigate technological applications for nucleic acids. Through organic synthesis, modification of the nucleic acid scaffold can be achieved leading to molecules with increased functionality for a broad range of applications that can improve our society.One avenue of nucleic acid based research that our group will explore involves investigation of the relationship between modification/damage to the information content of DNA with the response of DNA repair proteins. The importance of DNA repair was endorsed by the scientific community with the 2015 Nobel Prize in Chemistry awarded to Lindahl, Modrich and Sancar for their contributions to our understanding of DNA repair pathways. Our laboratory has been interested in exploring the ability of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) to act upon on a variety of modified nucleic acid structures prepared by organic synthesis. AGTs can remove alkylation damage from the O6-atom of 2'-deoxyguanosine and O4-atom of thymidine with differences in repair efficiency towards these lesions depending on the source of the AGT (i.e. Human versus E. coli). To address this issue, we will explore the influence of various groups at the C5-position of thymidine on AGT repair. We will also explore AGT repair of intrastrand cross-link lesions in G-quadruplex structures. These findings will enhance our knowledge of substrates that AGT, a protein important for health and growing applications in biotechnology, can process. Our group will study the processing of DNA damage by bypass polymerases with chemically synthesized analogs of DNA damage resulting from reactive nitrogen species and investigate the influence of nucleobase orientation on nucleotide incoportation. Understanding the mechanisms by which these proteins bypass damage provides important insights explaining why some forms of damage offer such a challenge for the cell to repair. We will study ways to stabilize the parallel stranded duplex formed by polyadenosine, a structure that is of interest for applications in nucleic acid nanoscience. Also, we will develop methods for incorporation of selenium into nucleic acids to add to the toolbox of methods for structure determination by X-ray crystallography.Canada has a very active and growing research community in the field of nucleic acid chemistry. This research program will provide multidisciplinary training in the fields of organic chemistry and biochemistry to the next generation of scientists embarking in this important field of science.
脱氧核糖核酸(DNA)和核糖核酸(RNA)是生命的核心分子。沃森和克里克在60多年前描述的DNA双螺旋结构的发现继续导致生物学和医学的许多进步。最近,这种优雅的结构及其特定相互作用的性质激发了科学家和工程师研究核酸的技术应用。通过有机合成,可以实现核酸支架的修饰,从而使分子具有更高的功能性,从而改善我们的社会。我们小组将探索的基于核酸的研究的一个途径是调查DNA信息内容的修饰/损伤与DNA修复蛋白的反应之间的关系。DNA修复的重要性得到了科学界的认可,2015年诺贝尔化学奖授予了Lindahl,Modrich和Sancar,以表彰他们对我们理解DNA修复途径的贡献。我们的实验室一直有兴趣探索的能力,DNA修复蛋白O 6-烷基鸟嘌呤-DNA烷基转移酶(AGT)的作用于各种修饰的核酸结构制备的有机合成。AGT可以从2 '-脱氧鸟苷的O 6-原子和胸苷的O 4-原子去除烷基化损伤,对这些损伤的修复效率取决于AGT的来源(即人与E.大肠杆菌)。为了解决这个问题,我们将探讨在C5-位置的胸苷AGT修复的各种基团的影响。 我们还将探讨AGT修复G-四链体结构中的链内交联损伤。这些发现将增强我们对AGT底物的了解,AGT是一种对健康和生物技术日益增长的应用很重要的蛋白质,可以加工。 我们的研究小组将研究由旁路聚合酶与化学合成的类似物的DNA损伤导致的活性氮物种的DNA损伤的处理,并调查核碱基的方向对核苷酸inportation的影响。 了解这些蛋白质绕过损伤的机制提供了重要的见解,解释了为什么某些形式的损伤为细胞修复提供了如此大的挑战。我们将研究如何稳定由聚腺苷形成的平行链双链体,这种结构在核酸纳米科学中的应用很有兴趣。 此外,我们将开发将硒掺入核酸的方法,以增加X射线晶体学结构测定方法的工具箱。加拿大在核酸化学领域有一个非常活跃和不断增长的研究团体。该研究计划将提供有机化学和生物化学领域的多学科培训,为下一代科学家从事这一重要的科学领域。

项目成果

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Wilds, Christopher其他文献

Wilds, Christopher的其他文献

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{{ truncateString('Wilds, Christopher', 18)}}的其他基金

Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
  • 批准号:
    RGPIN-2017-06683
  • 财政年份:
    2021
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Discovery Grants Program - Individual
Urgent Replacement of a Biomolecular Imager For Bioorganic and Biological Chemistry Research
紧急更换用于生物有机和生物化学研究的生物分子成像仪
  • 批准号:
    RTI-2021-00470
  • 财政年份:
    2020
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Research Tools and Instruments
Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
  • 批准号:
    RGPIN-2017-06683
  • 财政年份:
    2020
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Discovery Grants Program - Individual
Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
  • 批准号:
    RGPIN-2017-06683
  • 财政年份:
    2019
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Discovery Grants Program - Individual
Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
  • 批准号:
    RGPIN-2017-06683
  • 财政年份:
    2018
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Discovery Grants Program - Individual
Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
  • 批准号:
    RGPIN-2017-06683
  • 财政年份:
    2017
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Discovery Grants Program - Individual
Synthesis and investigation of modified oligonucleotides as probes of DNA repair
作为 DNA 修复探针的修饰寡核苷酸的合成和研究
  • 批准号:
    299384-2011
  • 财政年份:
    2016
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Discovery Grants Program - Individual
Synthesis and investigation of modified oligonucleotides as probes of DNA repair
作为 DNA 修复探针的修饰寡核苷酸的合成和研究
  • 批准号:
    299384-2011
  • 财政年份:
    2014
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Discovery Grants Program - Individual
Biological Chemistry
生物化学
  • 批准号:
    1000213807-2009
  • 财政年份:
    2013
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Canada Research Chairs
Synthesis and investigation of modified oligonucleotides as probes of DNA repair
作为 DNA 修复探针的修饰寡核苷酸的合成和研究
  • 批准号:
    299384-2011
  • 财政年份:
    2013
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Discovery Grants Program - Individual

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Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
  • 批准号:
    RGPIN-2017-06683
  • 财政年份:
    2021
  • 资助金额:
    $ 3.28万
  • 项目类别:
    Discovery Grants Program - Individual
Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
  • 批准号:
    RGPIN-2017-06683
  • 财政年份:
    2020
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    $ 3.28万
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Development of amido-bridged nucleic acid-modified antisense oligonucleotides to treat gastrointestinal malignancies
开发酰胺桥核酸修饰的反义寡核苷酸来治疗胃肠道恶性肿瘤
  • 批准号:
    20K21629
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    2020
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Development of modified nucleic acid possessing RNase H activity for antisense oligonucleotides without phosphorothioate (PS) modification
开发具有 RNase H 活性的反义寡核苷酸修饰核酸,无需硫代磷酸酯 (PS) 修饰
  • 批准号:
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Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
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Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
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    RGPIN-2017-06683
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Modified Nucleic Acid Structures to Interrogate Biochemical Processes and Design Principles of Responsive Nanodevices
修饰核酸结构以探究响应性纳米器件的生化过程和设计原理
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    RGPIN-2017-06683
  • 财政年份:
    2017
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    $ 3.28万
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    Discovery Grants Program - Individual
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