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)

• 批准号: 2750079
• 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

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cardiovascular adverse drug reaction warnings and 1 in 7 licensed drugs deemed efficacious in phase III trials are withdrawn from the market.This collaborative project is joint between Universities of Nottingham and Birmingham, AstraZeneca and GlaxoSmithKline.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，心血管疾病是导致死亡的主要原因，其中潜在的基因突变、合并症和药物引起的脱靶心脏毒性尤其麻烦。不适当的测试模型掩盖了这些问题。前 200 种药物占美国每年 43 亿张处方的 66.6%。然而，81 种药物是黑盒的，82 种药物带有心血管不良反应警告，在 III 期试验中被认为有效的许可药物中，有七分之一被撤出市场。该合作项目是诺丁汉大学和伯明翰大学、阿斯利康和葛兰素史克联合开展的。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、机器人学、药理学、转录组学和生物信息学/编码/人工智能。我们发表的工作开创性地在 hiPSC 中进行 CRISPR 基因编辑，以创建导致肥厚性心肌病 (HCM) 的变异体，这是一种与相当大的发病率和死亡率相关的复杂异质性疾病。将结合不同的技能组合和培训来完成 3 个目标，旨在未来定制和翻译药物患者遗传学治疗：- 为健康和患病（肥厚性心肌病；HCM）微组织建立基线结构/功能读数，这些微组织包含源自人类诱导多能干细胞的心血管谱系(hiPSC) - 量化患者相关药物挑战下的微组织结构/功能的变化 - 使用组学/人工智能方法获得机制洞察和途径信息，以改进药物使用。