Expanding the Druggable Human Genome

扩大可药物人类基因组

基本信息

批准号：
10653185
负责人：
Warren B Rouse
金额：
$ 4.08万
依托单位：
IOWA STATE UNIVERSITY
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：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653185
关键词：
2019-nCoV Algorithms Archives Area Binding Binding Sites Biochemical Bioinformatics Biological Assay Biology Bypass Cell Line Chemicals Code Collection Computer software DU145 Data Databases Disease Disease model Drug Design Drug Targeting Elements Engineering Gene Expression Genes Genetic Diseases Genome Health Human Human Genome Infection KRAS2 gene Knowledge Laboratories Malignant Neoplasms Maps Messenger RNA Methods Modeling Mosses Oncogenes Outcome Pathogenicity Pathway interactions Pharmaceutical Preparations Probability Proteins Proteome RNA RNA Binding RNA Probes RNA Viruses RNA-targeting therapy Research Research Personnel Resources Role Specificity Stress Structure Testing Therapeutic Therapeutic Intervention Transcript Translating Untranslated RNA Validation alpha synuclein bench to bedside cheminformatics comparative design drug action drug candidate drug discovery human pathogen improved innovation insight interest intermolecular interaction novel novel therapeutics nuclease precision medicine predictive modeling programs protein function recruit small molecule synergism targeted treatment tau Proteins therapeutic lead compound tool transcriptome vertebrate genome

项目摘要

PROJECT SUMMARY: Most small molecule drugs elicit their effects by modulating protein function, despite the fact that only a small portion of the genome is translated (~1-2%). Further, only ~15% of the human proteome is considered to be druggable, severely limiting therapeutic pipelines. The scientific challenge is to develop generalizable methods to drug the other ~85% of coding genes. The purpose of this proposal is to advance a radically new paradigm to expand the druggability of the (protein coding) genome by targeting disease-causing genes at the level of their RNA. To do so, we will computationally and biochemically determine RNA secondary structures in the transcriptome, with a focus on disease associated genes, to aid in the design of drug-like small molecules to treat diseases at the RNA level. This innovative approach for targeting the transcriptome could massively expand our ability to treat a wide array of diseases, spanning from genetic disorders to cancer and pathogenic infections, and expanding the repertoire of drug action. The proposed studies synergize the expertise of two laboratories. Dr. Walter Moss’ Lab (sponsor) has developed and implemented robust approaches to precisely define conserved and functional RNA structures throughout the human genome. Dr. Matthew Disney’s lab (co-sponsor) has established a comprehensive program for the design of small molecules that selectively target RNA and modulate disease biology, including those that selectively recruit endogenous nucleases to a desired transcript. Collectively, our synergistic areas of expertise will allow us to define the druggable human genome, drug undruggable protein targets at the level of their mRNAs, and push forward a bench-to-bedside, precision medicine paradigm. In Aim 1, we will define conserved RNA structures throughout the genome, with a focus on validating and targeting conserved structures in mRNAs that encode proteins that are considered undruggable. These studies will define evolutionary conservation across vertebrate genomes to provide key insights into both biology and druggability. We will evaluate and improve model structures using in cellulis RNA structure probing to test predictions and, where needed, provide constraints that can be used to create experimentally informed revised models. In Aim 2 we will generate a list of high value motifs with the highest probability of being druggable, perform functional analyses to determine their effects on gene expression, and deduce interactions.

项目摘要：大多数小分子药物通过调节蛋白质功能，dospite引起其作用仅翻译基因组的一小部分（〜1-2％）的事实。此外，只有约15％的人蛋白质组是被认为是可吸毒的，严重限制的治疗管道。科学挑战是发展其他约85％的编码基因吸毒的方法。该提议的目的是促进从根本上进行新的范式来扩展（蛋白质编码）基因组的可药用性，以靶向引起疾病基因在其RNA的水平上。为此，我们将在计算和生化确定的RNA次级转录组中的结构，侧重于疾病相关的基因，以帮助设计类似药物的小型分子以在RNA水平治疗疾病。针对转录组的这种创新方法可以从遗传疾病到癌症和致病感染，并扩大药物作用的曲目。拟议的研究协同两个实验室的专业知识。 Walter Moss博士（赞助商）开发和实施的可靠方法可以精确定义配置和功能性RNA结构整个人类基因组。 Matthew Disney博士实验室（共同赞助商）已建立了一个全面的针对选择性靶向RNA并调节疾病生物学的小分子设计程序，包括那些选择性地募集内源性核武器到所需的转录本。总的来说，我们的协同领域专业知识将使我们能够定义可吸毒的人类基因组，药物不良蛋白质靶标他们的mRNA，并推动了卧铺的精密医学范式。在AIM 1中，我们将在整个基因组中定义配置的RNA结构，重点是验证和靶向组成的MRNA结构，该结构编码被认为不可能的蛋白质。这些研究将定义跨脊椎动物基因组的进化保护，以提供对生物学和生物学的关键见解可药性。我们将在纤维素RNA结构探测中评估和改善模型结构进行测试预测以及在需要的情况下提供的约束，可用于创建实验知情的修订型号。在AIM 2中，我们将生成一个高价值基序的列表，其吸毒的可能性最高，进行功能分析以确定其对基因表达的影响并推断相互作用。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ScanFold 2.0: a rapid approach for identifying potential structured RNA targets in genomes and transcriptomes.

DOI：
10.7717/peerj.14361
发表时间：
2022
期刊：
PeerJ
影响因子：
2.7
作者：
Andrews RJ;Rouse WB;O'Leary CA;Booher NJ;Moss WN
通讯作者：
Moss WN

Thermodynamic and structural characterization of an EBV infected B-cell lymphoma transcriptome.

DOI：
10.1093/nargab/lqac082
发表时间：
2022-12
期刊：
NAR GENOMICS AND BIOINFORMATICS
影响因子：
4.6
作者：
O'Leary, Collin A.;Van Tompkins, S.;Rouse, Warren B.;Nam, Gijong;Moss, Walter N.
通讯作者：
Moss, Walter N.

Transcriptome-Wide Mapping of Small-Molecule RNA-Binding Sites in Cells Informs an Isoform-Specific Degrader of QSOX1 mRNA.

DOI：
10.1021/jacs.2c01929
发表时间：
2022-07-06
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Tong, Yuquan;Gibaut, Quentin M. R.;Rouse, Warren;Childs-Disney, Jessica L.;Suresh, Blessy M.;Abegg, Daniel;Choudhary, Shruti;Akahori, Yoshihiro;Adibekian, Alexander;Moss, Walter N.;Disney, Matthew D.
通讯作者：
Disney, Matthew D.

Expansion of the RNAStructuromeDB to include secondary structural data spanning the human protein-coding transcriptome.