Project 3 (Mercola)

总结 项目3：iPSC-CM筛选以发现机制和治疗靶点 心力衰竭（HF）是全球发病率和死亡率的主要原因，影响1-2%的美国人 这是一个重大的公共卫生负担。心力衰竭患者尤其 对心律失常敏感高达50%的HF患者死于心律失常和心源性猝死， 造成不稳定的健康风险，但很少有药物对这一人群有效。本PPG项目3 解决了与这些患者的临床管理相关的两个主要问题：1）为什么HF 特别易受药物诱导的心律失常影响的患者（目的1）和2）我们能否发现蛋白质 可以在药学上靶向创造全新类型的药物来治疗心律失常 这些患者（目标2和3）？ 我们将使用来自扩张型心肌病（DCM）患者的iPSC衍生的心肌细胞（项目1和2）。 CRISPR基因组编辑）作为研究蛋白质和信号传导水平机制的第一步， 以确定候选药物靶点。迄今为止，心肌细胞的生理学筛选缺乏 系统地探测机制和发现 治疗目标项目3将使用我们开发的仪器和iPSC-心肌细胞技术 在过去的十年里，我们克服了这一限制。从iPSC得出的结论- 心肌细胞的机制和候选药物靶点将在较低的吞吐量进行评估 成人心肌细胞制备（项目1和2）和多尺度计算建模 (with核心B），以确认和扩展假设，从而产生与完整的 人类的心脏 我们的团队，在项目和PPG，是高度协同和独特的适当执行这一点 大规模项目，应产生预防性可操作的见解，以最终改善患者 管理和创造更安全，更有效的治疗方法。

SUMMARY Project 3: iPSC-CM Screening to Discover Mechanisms and Therapeutic Targets Heart failure (HF) is major cause of morbidity and mortality worldwide and affects 1–2% of the US population and represents a major public health burden. Heart failure patients are particularly sensitive to arrhythmia. Up to 50% of HF patients die from arrhythmias and sudden cardiac death, creating a precarious health risk, yet few drugs are effective in this population. Project 3 of this PPG addresses two major questions relevant to the clinical management of these patients: 1) Why are HF patients particularly susceptible to drug-induced arrhythmia (Aim 1) and 2) Can we discover proteins that can be targeted pharmaceutically to create entirely new classes of drugs to treat arrhythmia in these patients (Aims 2 and 3)? We will use iPSC-derived cardiomyocytes from dilated cardiomyopathy (DCM) patients (Project 1 and CRISPR genome editing) as the first step to study mechanisms at the protein and signaling level and to identify candidate drug targets. To date, physiological screening of cardiomyocytes has lacked the throughput and prediction accuracy needed to systematically probe mechanisms and discover therapeutic targets. Project 3 will use instrument and iPSC-cardiomyocyte technology we developed over the last decade to overcome this limitation. The conclusions that will be drawn from iPSC- cardiomyocytes about mechanisms and candidate drug targets will be evaluated in lower throughput adult cardiomyocyte preparations (within Projects 1 and 2) and in multiscale computational modeling (with Core B) to confirm and extend hypotheses, thereby generating new insight relevant to the intact human heart. Our team, within the Project and PPG, is highly synergistic and uniquely appropriate to carry out this large-scale project that should yield translationally actionable insights to ultimately improve patient management and create safer, more effective therapeutics.