Chemical Approaches to Control the Function of Regulatory RNAs

控制调节性 RNA 功能的化学方法

• 批准号: 10548193
• 负责人: ERIKS ROZNERS
• 金额: $ 39.85万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548193
• 关键词: Address; Amides; Binding; Biological; Biological Models; Biological Sciences; Biology; CRISPR interference; Charge; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; DNA; Development; Disease; Double-Stranded RNA; Electrostatics; Goals; Hydrogen Bonding; Ligand Binding; Ligands; Medicine; MicroRNAs; Modification; Molecular Conformation; Oligonucleotides; Peptide Nucleic Acids; Pharmacy (field); Positioning Attribute; Productivity; Property; Proteins; RNA; RNA Binding; RNA Interference; Research; Small Interfering RNA; Specificity; Structure; Therapeutic; Untranslated RNA; Vertebral column; analog; design; genetic information; improved; inorganic phosphate; insight; novel; novel therapeutic intervention; novel therapeutics; programs; tool; triple helix; uptake

Recent decades have dramatically changed our view of RNA. While RNA was initially believed to be barely a passive messenger in the transfer of genetic information from DNA to proteins, it is now clear that RNA is an exciting and underexplored regulatory molecule that will continue to deliver new discoveries new discoveries in biology and medicine. Our research is focused on using chemical modifications to modulate the structure and function regulatory RNAs. The long-term goals are to 1) develop novel RNA chemical modifications for fundamental studies and biomedical applications, and 2) explore new modes of sequence- specific recognition of double-stranded RNA (dsRNA). Our research program comprises two distinct but interrelated projects: 1) amides as novel backbone modifications for regulatory RNAs, and 2) sequence- specific recognition of dsRNA by modified peptide nucleic acids (PNA). Project 1 replaces internucleotide phosphates with amide linkages in short interfering RNAs and RNAs associated with clustered regularly interspaced short palindromic repeats (CRISPR). The goals are to improve the cellular uptake, delivery and sequence specificity of these RNAs. The premise is that amides can mimic structure and H-bonding interactions of phosphates with proteins and, at certain positions, may be able to remodel and improve these interactions. Project 2 explores chemically modified PNA as a ligand for sequence-specific recognition of biomedically important dsRNA. The goals are to improve the cellular uptake of PNA and to demonstrate the biological effect of triplex formation using microRNAs as the initial model system. The premise is that M-modified triplex-forming PNAs are uniquely suited for sequence-specific recognition of dsRNA and will enable recognition of biologically important non-coding dsRNA. Future research will focus on chemical modifications of CRISPR RNAs and using the triple helix to control conformations of complex non-coding RNAs. The two projects share a common theme of designing chemical modifications that take advantage of charge complementarity between the RNA target and the ligands and proteins interacting with RNA. The overreaching idea is to develop RNA chemical modifications and RNA binding ligands that avoid unproductive electrostatic repulsion and capitalize on productive electrostatic attraction while concurrently enhancing sequence specificity of molecular interactions. This thrust grows out of our recent discoveries that RNA is unusually receptive to chemical modifications that neutralize the negative charge of phosphate backbone, both in RNA itself and in RNA binding oligonucleotide analogues. If successful, our research will contribute to addressing key gaps in RNA interference, CRISPR, recognition of therapeutically relevant RNAs, and will open doors for development of unique research tools and new therapeutic strategies.

近几十年来，我们对RNA的看法发生了巨大的变化。而RNA最初被认为几乎不存在