Identifying novel & repurposing drug targets for Atrial Fibrillation MEDicines

识别小说

• 批准号: EP/Z000211/1
• 负责人: Amand Schmidt
• 金额: $ 220.34万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FZ000211%2F1
• 关键词: Identifying; novel; repurposing; drug; targets

Atrial fibrillation (AF) is an arrhythmia of the upper chambers of the heart (i.e. atria) which is characterized by loss of organized contraction. AF is the most frequent cause of sustained arrhythmia, and will affect at least a third of the population at some point. Despite improvements in healthcare delivery and public health, AF is a growing global epidemic, which is forecasted to affect over 18 million people aged 55+ in Europe by 2060 (more than double the number of individuals in 2010: 8.8 million). Clinical outcomes of AF vary considerably, from a single episode, to persistent arrythmia resulting in serious complications and mortality. People with AF are at an increased risk of developing multiple comorbidities, such as lung disease, kidney insufficiencies, cardioembolic stroke, cognitive decline and vascular dementia. Treatment for AF is limited, where since the 2015 introduction of the oral anticoagulants rivaroxaban, apixaban and edoxaban, no novel compounds have been approved.To help re-invigorate AF drug development I propose to develop a novel "multi-modal" research line, combining different data types such as proteomics, metabolomics, genomic and imaging modalities, as well as include distinct analytical methods spanning genetic epidemiology, real-world observational studies, and biological network analysis. Specifically, I propose to leverage my strong background in genetics, pharmaco-epidemiology, and machine learning to explore determinants of AF and AF-related comorbidity to identify (novel and repurposing) drug targets for improved disease management. I will improve AF management by 1) exploring imaging and biomarker disease surrogates, 2) identifying protein drug targets, 3) identify druggable genes associating with atrial ablation traits, 4) evaluating real-world evidence on repurposing candidates, and 5) create knowledge graphs to prioritize AF drug targets by combining genetic and non-genetic evidence.

心房颤动 (AF) 是心脏上腔室（即心房）的一种心律失常，其特征是有组织的收缩丧失。房颤是持续性心律失常的最常见原因，并且在某些时候会影响至少三分之一的人口。尽管医疗保健服务和公共卫生有所改善，房颤仍是一种日益严重的全球流行病，预计到 2060 年，欧洲 55 岁以上的人口将超过 1800 万人（是 2010 年人数的两倍多：880 万人）。房颤的临床结果差异很大，从单次发作到持续性心律失常，导致严重的并发症和死亡。房颤患者出现多种合并症的风险增加，例如肺病、肾功能不全、心源性中风、认知能力下降和血管性痴呆。房颤的治疗方法有限，自 2015 年推出口服抗凝剂利伐沙班、阿哌沙班和艾多沙班以来，尚未批准任何新化合物。为了帮助重振房颤药物开发，我建议开发一种新型“多模式”研究线，结合不同的数据类型，如蛋白质组学、代谢组学、基因组和成像模式，以及涵盖遗传流行病学、现实世界观察研究的不同分析方法，和生物网络分析。具体来说，我建议利用我在遗传学、药物流行病学和机器学习方面的强大背景来探索房颤和房颤相关合并症的决定因素，以确定（新颖的和重新利用的）药物靶点，以改善疾病管理。我将通过以下方式改善房颤管理：1) 探索影像学和生物标志物疾病替代物，2) 识别蛋白质药物靶点，3) 识别与心房消融特征相关的可药物基因，4) 评估重新利用候选药物的现实世界证据，以及 5) 创建知识图通过结合遗传和非遗传证据来优先考虑 AF 药物靶点。