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 - 基因组学药物：药物重新定位和功能测试以预防 房颤进展 项目概要 心房颤动 (AF) 的一个重要临床问题是防止 AF 进一步发展为持续性 形式。首次发作后，房颤复发，负担增加约 50%，并进展至 25% 的人在诊断后 5 年内发生持续性或永久性 AF。与阵发性 AF 相比， 对于持续或消融的患者，预后较差，药物或消融治疗后的结果更差 永久自动对焦。虽然许多过程和途径与 AF 的发展有关，但影响较小 进展的程度、精确的分子驱动因素、它们的相互作用以及它们作用的背景并不完全 明白了。发生 AF 的遗传风险因素可能不同于促进 AF 进展的遗传风险因素， 这也可能受到环境、共病或细胞应激源的影响。我们假设一个 可以识别 AF 进展与基因调控和相互作用网络之间的相互作用，并且 了解这些机制对于了解 AF 进展的治疗发现至关重要。我们的目标 是确定 AF 进展基因、途径和模块，从而能够识别并验证 用于预防 AF 和 AF 进展的可重复使用药物。为了找到针对 AF 进展的药物，我们 首先必须更好地了解 AF 进展的分子组成部分。该项目建立在我们之前的基础上 人类左心耳 (LA) 组织中的 RNA 测序 (RNASeq) 数据显示出改变， 随着进展，细胞应激途径的转录组反应不足或不堪重负 持续自动对焦。我们建议将单核转录组学 (snRNASeq) 整合到人类 LA 组织中 识别主转录因子 (TF) 和相互作用组介导的基因调控网络和细胞类型 潜在的 AF 疾病进展，克服了批量 RNASeq 数据无法解析变化的限制 来自不同的细胞组成，例如成纤维细胞，可能会随着 AF 的进展而增加。 snRNASeq 将 进一步了解 AF 进展以及与进展相关的特定细胞类型。我们还将利用人类 相互作用组网络方法识别随 AF 变化的新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、蛋白质组和 使用人工智能 (AI) 方法的代谢组学数据来确定 AF 进展的治疗靶点 以及针对 AF 进展的可重复利用药物和药物组合。 '来自其他项目的组学数据 还将整合可能产生潜在基因或途径特异性候选药物的计划。候选人 然后，药物和组合将在人体工程心脏组织（EHT）和相关药物中进行功能测试 自发性房颤和房颤进展的小鼠模型。我们对识别可重复利用药物的关注将 缩短 AF 测试时间。该项目的成功完成将为分子生物学提供深入的见解。 房颤进展的机制； AF 的药物鉴定、功能测试和验证流程 房颤进展；重要的是，药物已准备好进行临床测试。