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Synthesis of Sensitive Epitranscriptomically Modified RNAs

敏感表观转录组修饰 RNA 的合成

基本信息

批准号：
10730262
负责人：
Shiyue Fang
金额：
$ 45.15万
依托单位：
MICHIGAN TECHNOLOGICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730262
关键词：
Address Affect Area Biological Biological Process Biomedical Research Chemicals Communities Data Development Diabetes Mellitus Disease Enzymes Evaluation Excision Foundations Goals Knowledge Link Machine Learning Medicine Messenger RNA MicroRNAs Modeling Modification Molecular Nature Neurodegenerative Disorders Nucleic Acids Nucleosides Obesity Organism Pathology Phase Prevention Property Protein Biosynthesis Proteins RNA RNA Degradation RNA Stability RNA chemical synthesis RNA-Protein Interaction Reading Research Personnel Research Project Grants Ribosomal RNA Role S phase Sampling Small Nuclear RNA Small Nucleolar RNA Solid Structure Sulfur Technology Thermodynamics Time Training Transfer RNA Translations Writing acyl group amino group base biophysical properties chemical synthesis diagnostic tool disease diagnosis epitranscriptomics functional group human disease innovation leukemia monomer nanopore new technology new therapeutic target nucleobase oxidation single molecule success tool transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract The objective of this project is to develop a solid phase technology that is universally useful for the synthesis of epitranscriptomically modified RNAs containing sensitive functional groups. Sensitive functional groups here refers to those that are unstable under the basic and nucleophilic conditions widely used for deprotection and cleavage in existing chemical RNA synthesis technologies. Many naturally occurring RNAs including tRNA, rRNA, mRNA, snRNA, snoRNA, miRNA and lncRNA contain such sensitive groups. They have important biological functions, and errors related to their installation, reading and erasing are associated with human diseases. To obtain the knowledge such as the mechanisms by which the sensitive groups modulate RNA biophysical properties and RNA-protein interactions, and the pathology of diseases involving sensitive groups, chemical synthesis of the sensitive RNAs are needed. Currently many such RNAs cannot be synthesized by any existing technologies. The objective of this project is to fill this technology gap. Using a new set of solid phase synthesis linkers and protecting groups, RNAs will be synthesized, cleaved and deprotected under mild conditions under which almost all sensitive groups found in living systems so far are stable, and thus the new technology will be capable to synthesize almost all naturally occurring sensitive RNAs. To illustrate the predicted broad impact of the sensitive RNA synthesis technology, model mRNAs containing the sensitive ac4C modification will be synthesized using the technology. Dysregulations of ac4C have been linked to many human diseases including leukemia, diabetes, obesity and neurodegenerative diseases. Recent studies found that ac4C in mRNA enhances protein synthesis, but the molecular mechanism is unknown. The ac4C-containing model mRNAs will be used to fill this knowledge gap. The new knowledge is expected to be useful in areas such as identification of new therapeutics targets for treating various human diseases, and evaluation of the potential of ac4C-containing RNAs as medicines. Beyond this specific example, with the access to a wide range of sensitive RNAs, many other biomedical projects such as the identification of proteins responsible for reading and erasing various RNA modifications, the use of RNAs containing sensitive modification as training samples for machine learning in nanopore single molecule RNA sequencing, and deciphering mechanisms by which sensitive groups regulate RNA degradation and protein synthesis, all of which are impossible or challenging to do at this time, will become possible for the biomedical research community.

项目总结/摘要本项目的目标是开发一种普遍适用于合成的固相技术含有敏感官能团的表转录修饰RNA。这里的敏感官能团是指在广泛用于脱保护的碱性和亲核条件下不稳定的那些，在现有的化学RNA合成技术中切割。许多天然存在的RNA包括tRNA， rRNA、mRNA、snRNA、snoRNA、miRNA和lncRNA含有这样的敏感基团。具有重要的生物学功能以及与它们的安装、阅读和擦除相关的错误与人类有关。疾病获得敏感基团调节RNA的机制等知识生物物理特性和RNA-蛋白质相互作用，以及涉及敏感群体的疾病的病理学，需要化学合成敏感的RNA。目前，许多这样的RNA不能由任何生物合成。现有技术。该项目的目标是填补这一技术空白。使用一组新的固相为了合成接头和保护基团，RNA将在温和的条件下合成、切割和脱保护，在这种条件下，迄今为止在生命系统中发现的几乎所有敏感群体都是稳定的，因此，技术将能够合成几乎所有天然存在的敏感RNA。为了说明预测的敏感RNA合成技术的广泛影响，包含敏感ac 4C的模型mRNA 将使用该技术合成改性。ac 4C的调节异常与许多人类疾病有关。疾病包括白血病、糖尿病、肥胖症和神经变性疾病。最近的研究发现，ac 4c 在mRNA中，增强蛋白质合成，但分子机制尚不清楚。含ac 4c模型 mRNA将被用来填补这一知识空白。新知识预计将在以下领域发挥作用，鉴定用于治疗各种人类疾病的新治疗靶点，并评估含有ac 4C的RNA作为药物。除了这个具体的例子，随着对广泛的敏感 RNA，许多其他生物医学项目，如识别负责阅读和擦除的蛋白质各种RNA修饰，使用含有敏感修饰的RNA作为机器训练样本，纳米孔单分子RNA测序的学习，以及敏感群体调节RNA降解和蛋白质合成，所有这些在目前都是不可能或具有挑战性的，将成为生物医学研究界的可能。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oligonucleotide synthesis under mild deprotection conditions

温和脱保护条件下的寡核苷酸合成

DOI：
10.1039/d2nj03845e
发表时间：
2023
期刊：
New Journal of Chemistry
影响因子：
3.3
作者：
Chillar, Komal;Eriyagama, Adikari M.;Yin, Yipeng;Shahsavari, Shahien;Halami, Bhaskar;Apostle, Alexander;Fang, Shiyue
通讯作者：
Fang, Shiyue

dM-Dim for Carboxylic Acid Protection.

dM-Dim 用于羧酸保护。

DOI：
10.1016/j.tetlet.2018.03.076
发表时间：
2018
期刊：
Tetrahedron letters
影响因子：
1.8
作者：
Shahsavari,Shahien;Wigstrom,Travis;Gooding,James;McNamara,Chase;Fang,Shiyue
通讯作者：
Fang,Shiyue

Sensitive Oligodeoxynucleotide Synthesis Using Dim and Dmoc as Protecting Groups.

DOI：
10.1021/acs.joc.9b01527
发表时间：
2019-09
期刊：
The Journal of organic chemistry
影响因子：
0
作者：
Shahien Shahsavari;Dhananjani N A M Eriyagama;Jinsen Chen;Bhaskar Halami;Yipeng Yin;Komal Chillar;Shiyue Fang
通讯作者：
Shahien Shahsavari;Dhananjani N A M Eriyagama;Jinsen Chen;Bhaskar Halami;Yipeng Yin;Komal Chillar;Shiyue Fang

Solid Phase Stepwise Synthesis of Polyethylene Glycols.