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Unravelling drug-gene-phenotype interactions in complex cardiovascular diseases (iCASE)

揭示复杂心血管疾病中的药物-基因-表型相互作用 (iCASE)

基本信息

批准号：
2750079
负责人：
金额：
--
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2750079
关键词：
Unravelling drug gene phenotype interactions

项目摘要

Globally, cardiovascular disease is the leading cause of death, with underlying genetic mutations, comorbidities and drug-induced off-target cardiotoxicity being especially troublesome. Inappropriate testing models belie these issues. The top 200 drugs account for 66.6% of the 4.3bn prescriptions in the USA/pa. Yet, 81 are black boxed, 82 carry cardiovascular adverse drug reaction warnings and 1 in 7 licensed drugs deemed efficacious in phase III trials are withdrawn from the market.This collaborative project is joint between Universities of Nottingham and Birmingham, AstraZeneca and GlaxoSmithKline. Collective interdisciplinary experience spans human induced pluripotent stem cells (hiPSCs), differentiation to cardiovascular linages, molecular/functional phenotyping, robotics, pharmacology, transcriptomics and bioinformatics/coding/AI. Our published work pioneered CRISPR gene editing in hiPSC to create variants that cause hypertrophic cardiomyopathy (HCM), a complex heterogeneous disease associated with considerable morbidity and mortality.Diverse skillsets and training will be combined to complete 3 objectives, aimed at future tailoring and translating drug therapy to patient genetics:- Establish baseline structure/functional readouts for healthy and diseased (hypertrophic cardiomyopathy; HCM) microtissues comprising cardiovascular lineages derived from human induced pluripotent stem cells (hiPSCs)- Quantify changes in microtissue structure/function challenged with patient-relevant drugs- Use omics/AI approaches for mechanistic insight and pathways information to refine drug use.

在全球范围内，心血管疾病是死亡的主要原因，潜在的基因突变，合并症和药物诱导的脱靶心脏毒性尤其令人担忧。不适当的测试模型掩盖了这些问题。排名前200位的药物占美国43亿张处方的66.6%/pa。然而，81个是黑盒子，82个带有心血管药物不良反应警告，七分之一在III期试验中被认为有效的许可药物被撤回市场。这个合作项目是诺丁汉和伯明翰大学，阿斯利康和葛兰素史克之间的联合。集体跨学科经验涵盖人类诱导多能干细胞（hiPSC），心血管谱系分化，分子/功能表型，机器人，药理学，转录组学和生物信息学/编码/AI。我们发表的工作开创了hiPSC中的CRISPR基因编辑，以创建导致肥厚性心肌病（HCM）的变体，HCM是一种与相当高的发病率和死亡率相关的复杂异质性疾病。不同的技能和培训将结合起来，以完成3个目标，旨在未来定制并将药物治疗转化为患者遗传学：（肥厚型心肌病; HCM）微组织，包含源自人诱导多能干细胞（hiPSC）的心血管谱系-定量用患者相关药物激发的微组织结构/功能的变化-使用组学/人工智能方法用于机械洞察和途径信息，以改进药物使用。