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Chemical approaches for precision genome editing

精确基因组编辑的化学方法

基本信息

批准号：
10211408
负责人：
Amit Choudhary
金额：
$ 34.75万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211408
关键词：
Acetyltransferase Affinity Base Pairing Binding Biomedical Technology CRISPR/Cas technology Cells Charge Chemicals Chromosomal translocation Clustered Regularly Interspaced Short Palindromic Repeats Complex Cysteine DNA DNA Binding Deacetylase Deoxyribonuclease I Development Dose Engineering Enzymes Esterification Gene Therapy Agent Genetic Transcription Genome Genome engineering Genomics Guide RNA HIV Hereditary Disease Hydrophobicity Image Impairment Laboratories Light Lysine Mammalian Cell Methods Modification Muscular Dystrophies Pathology Performance Permeability Proteins Proteome Rain Reagent Reporting Repression Ribonucleases Scheme Site Specificity Structure Structure-Activity Relationship System Technology Time Toxic effect Transcription Coactivator Transcription Repressor Transcriptional Activation Ursidae Family Vision Disorders base chemical genetics chemoproteomics endonuclease epigenome editing esterase gene repression gene therapy genetic approach genome editing genomic locus genotoxicity improved inhibitor/antagonist mimetics nanomolar nuclease personalized approach programs small molecule small molecule inhibitor targeted nucleases

项目摘要

PROJECT SUMMARY CRISPR-Cas9 is an RNA-guided endonucleases that is being actively used for sequence-specific DNA recognition, genome engineering, targeted transcriptional activation/repression and genome imaging. Cas9 is being developed as a gene therapy agent for multiple pathologies, including HIV, vision disorders, muscular dystrophy, and hereditary disorders. The precision control of specificity of CRISPR-Cas9 is required as off- target effects and chromosomal translocations are observed at elevated activity. Further, the ease of targeting catalytically impaired Cas9 to any genomic locus has resulted in transformative technologies. For example, the fusion of catalytically inactive Cas9 (dCas9) to transcriptional activators or repressors has enabled gene transcription and repression; fusion of catalytically impaired Cas9 to base-modifying enzymes has allowed base conversion (e.g., C→T) at specific genomic sites; dCas9‒GFP fusion has made imaging genomic loci possible; and dCas9‒acetyltransferases or deacetylases fusion has enabled epigenome editing. We propose to apply chemical and genetic approaches develop reagents and methods that will allow precision control of specificity of CRISPR-Cas9. 1

项目摘要 CRISPR-Cas9是一种RNA引导的核酸内切酶，被积极用于序列特异性DNA测序。识别、基因组工程、靶向转录激活/抑制和基因组成像。Cas9是作为一种基因治疗剂正在开发的多种病理，包括艾滋病毒，视力障碍，肌肉营养不良和遗传性疾病。CRISPR-Cas9的特异性的精确控制是必需的，在升高的活性下观察到靶向效应和染色体易位。此外，瞄准目标的容易性催化受损的Cas9与任何基因组基因座的结合导致了变革性技术。比如说无催化活性的Cas9（dCas 9）与转录激活因子或阻遏物的融合使基因转录和阻遏;催化受损的Cas9与碱基修饰酶的融合允许碱基修饰酶的表达。转换（例如，C→T）; dCas 9与GFP融合使基因组位点成像成为可能; 和dCas 9的乙酰转移酶或脱乙酰酶融合使得表观基因组编辑成为可能。我们建议申请化学和遗传学方法开发了允许精确控制特异性的试剂和方法 CRISPR-Cas9 1