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.

项目摘要/摘要该项目的目的是开发一种固相技术，该技术普遍有用含有敏感官能基团的表面转录修饰的RNA。敏感的官能团在这里是指在基本和亲核条件下广泛用于脱保护和现有化学RNA合成技术中的裂解。许多天然发生的RNA，包括tRNA， rRNA，mRNA，snRNA，SNORNA，miRNA和lncRNA包含此类敏感组。他们很重要生物学功能以及与其安装，阅读和擦除有关的错误与人类有关疾病。为了获得知识，例如敏感组调节RNA的机制生物物理特性和RNA - 蛋白质相互作用，以及涉及敏感组的疾病的病理，需要敏感RNA的化学合成。目前，许多这样的RNA不能由任何人合成现有技术。该项目的目的是填补这一技术空白。使用新的固相综合接头和保护组，RNA将在轻度下合成，切割和脱落到目前为止，几乎所有敏感群体都稳定的条件都稳定，因此是新的技术将能够综合几乎所有自然发生的敏感RNA。为了说明预测敏感RNA合成技术的广泛影响，模型含有敏感AC4C的mRNA 修改将使用该技术合成。 AC4C的失调与许多人有关包括白血病，糖尿病，肥胖和神经退行性疾病在内的疾病。最近的研究发现AC4C 在mRNA中可以增强蛋白质的合成，但分子机制尚不清楚。含AC4C的模型 mRNA将用于填补这一知识差距。预计新知识将在诸如确定用于治疗各种人类疾病的新疗法靶标的含AC4C的RNA作为药物。除了这个具体的例子之外，还可以访问广泛的敏感 RNA，许多其他生物医学项目，例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作为机器的训练样品在纳米孔单分子RNA测序和敏感基团的解密机制中学习调节RNA降解和蛋白质合成，目前所有这些都是不可能或具有挑战性的，生物医学研究界将有可能。

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.