Project 3 Genes to Omics-Informed Drugs: Drug Repositioning and Testing to Prevent AF Progressions

项目 3 基因组学药物：药物重新定位和测试以预防 AF 进展

• 批准号: 10410650
• 负责人: Mina Kay Chung
• 金额: $ 62.14万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410650
• 关键词: Ablation; Algorithms; Artificial Intelligence; Atrial Fibrillation; Bass; Cell Nucleus; Cell model; Cells; Cellular Stress; Cessation of life; Clinical; Data; Databases; Development; Diagnosis; Disease; Disease Progression; Doctor of Philosophy; Drug Combinations; Drug Targeting; Electrophysiology (science); Fibroblasts; Gene Expression; Genes; Genetic; Genomics; Goals; Heart Atrium; Human; Human Engineering; Lead; Left; Measures; Mediating; Medical; Metabolic; Methodology; Modeling; Molecular; Molecular Disease; Multiomic Data; Mus; Network-based; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Prevention; Process; Prognosis; Proteins; Proteomics; Recurrence; Regulator Genes; Stress; Systems Biology; Testing; Therapeutic; Time; Tissue Model; Tissues; Validation; appendage; auricular appendage; base; biobank; cardiac tissue engineering; cell type; comorbidity; drug candidate; drug development; drug testing; gene regulatory network; genetic risk factor; genome wide association study; human interactome; insight; metabolomics; mouse model; multimodality; novel; personalized medicine; precision medicine; preclinical efficacy; prevent; programs; research clinical testing; response; risk variant; side effect; stressor; success; therapeutic target; transcription factor; transcriptome sequencing; transcriptomics; trial design

PROJECT 3 - Genes to Omics-Informed Drugs: Drug Repositioning and Functional Testing to Prevent AF Progression PROJECT SUMMARY An important clinical problem in atrial fibrillation (AF) is preventing AF from progressing to more persistent forms. After an initial episode, AF recurs with increase in burden occurring in ~50% and progression to persistent or permanent AF occurring in 25% within 5 years of diagnosis. Compared to paroxysmal AF, prognosis is poorer and outcomes after medical or ablation therapy are worse for patients with persistent or permanent AF. While many processes and pathways have been implicated in AF development and to a lesser extent progression, the precise molecular drivers, their interactions and context in which they act are not fully understood. Genetic risk factors for development of AF may differ from those promoting progression of AF, which may also be impacted by environmental, comorbid or cellular stressors. We hypothesize that an interplay between AF progression and gene regulatory and interactome networks can be identified and that understanding these mechanisms is essential to informing therapeutic discovery for AF progression. Our goal is to identify AF progression genes, pathways and modules that will enable identification and then validation of repurposable drugs for the prevention of AF and AF progression. To find drugs to target progression of AF, we must first better understand the molecular components of AF progression. This project builds upon our prior RNA sequencing (RNASeq) data in human left atrial (LA) appendage (LAA) tissues that showed altered, inadequate or overwhelmed transcriptomic responses to cell stress pathways occur with progression to persistent AF. We propose to integrate single-nucleus transcriptomics (snRNASeq) in human LA tissue to identify master transcription factor (TF)- and interactome-mediated gene regulatory networks and cell types underlying AF disease progression, overcoming a limitation of bulk RNASeq data that cannot resolve changes from differing cell composition, such as fibroblasts, which may increase with AF progression. snRNASeq will yield further insights into AF progression and specific cell types related to progression. We will also use human interactome network approaches to identify novel risk genes and disease modules that change with AF progression. We will then integrate interactome, genetic, and AF progression genomic, proteomic and metabolomics data using artificial intelligence (AI) approaches to identify therapeutic targets for AF progression and repurposable drugs and drug combinations targeting AF progression. ‘Omic data from other projects in the Program will also be integrated that may yield potential gene or pathway specific candidate drugs. Candidate drugs and combinations will then be functionally tested in human engineered heart tissues (EHTs) and relevant mouse models of spontaneous AF and AF progression. Our focus on identifying repurposable drugs will shorten the time to testing for AF. Successful completion of this Project will provide insights into the molecular mechanisms of AF progression; a pipeline for drug identification, functional testing and validation for AF and AF progression; and importantly, drugs ready for clinical testing.

项目3-对OMICS知名药物的基因：药物重新定位和功能测试以防止 AF的进展 项目摘要 房颤（AF）中一个重要的临床问题是防止AF发展到更持久 表格。首次发作后，AF复发，燃烧的增加在〜50％，进展为 诊断后的5年内，持续或永久性AF发生在25％。与阵发性AF相比 预后较差，医疗或消融治疗后的结果对于持续或 永久AF。尽管许多过程和途径在AF开发中已实施，并且较小 范围进展，精确的分子驱动因素，它们的相互作用和作用的背景不完全 理解。 AF发展的遗传危险因素可能与促进AF进展的遗传风险因素不同， 这也可能受到环境，合并或细胞应激源的影响。我们假设 可以确定AF进展与基因调节和相互作用网络之间的相互作用，并且 了解这些机制对于为AF进展的治疗发现提供了必要。我们的目标 是识别AF进度基因，途径和模块，以实现识别然后验证 用于预防AF和AF进展的可重新申请药物。为了找到靶向AF进展的药物，我们 首先必须更好地了解AF进展的分子成分。这个项目建立在我们先前的 人类左心房（LA）附属组织（LAA）组织中的RNA测序（RNASEQ）数据，显示出改变， 对细胞应激途径的不足或不足的转录组反应随着发展而发生 持续的AF。我们建议将人LA组织中的单核转录组学（SNRNASEQ）整合到 识别主转录因子（TF） - 以及相互作用介导的基因调节网络和细胞类型 基本的AF疾病进展，克服无法解决变化的批量RNASEQ数据的局限性 来自不同细胞组成，例如成纤维细胞，可能随着AF进展而增加。 snrnaseq会 对AF进展和与进展相关的特定细胞类型产生进一步的见解。我们还将使用人类 相互作用的网络方法来识别随着AF改变的新型风险基因和疾病模块 进展。然后，我们将整合相互作用组，遗传和AF进展基因组，蛋白质组学和 使用人工智能（AI）方法来识别AF进展的治疗靶标的代谢组学数据 以及针对AF进展的可重申药物和药物组合。 ‘来自其他项目的OMIC数据 还将整合程序，以产生潜在的基因或途径特定候选药物。候选人 然后，将在人类工程心组织（EHT）和相关的人类工程心脏组织中进行功能测试药物和组合 赞助AF和AF进展的小鼠模型。我们专注于识别可再利用药物将 缩短测试AF的时间。该项目的成功完成将为分子提供见解 AF进展的机制；药物识别，功能测试和验证AF和验证的管道 AF进展；重要的是，准备进行临床测试的药物。