Project 3 (Mercola)

摘要 项目3：IPSC-CM筛查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，影响着美国1%-2%的地区 并且是一个主要的公共卫生负担。心力衰竭患者尤其 对心律失常敏感的。高达50%的心衰患者死于心律失常和心脏性猝死， 造成了不稳定的健康风险，但很少有药物在这一人群中有效。此PPG的项目3 解决与这些患者的临床管理相关的两个主要问题：1)为什么会发生心衰 对药物引起的心律失常特别敏感的患者(目标1)和2)我们能发现蛋白质吗？ 可以在药物上有针对性地创造出治疗心律失常的全新药物类别 这些患者(目标2和3)？ 我们将使用扩张型心肌病(DCM)患者的IPSC来源的心肌细胞(项目1和 CRISPR基因组编辑)作为在蛋白质和信号水平研究机制的第一步，以及 以确定候选药物目标。到目前为止，对心肌细胞的生理学筛选缺乏 需要吞吐量和预测精度来系统地探测机制和发现 治疗靶点。项目3将使用我们开发的仪器和IPSC-心肌细胞技术 在过去的十年中克服了这一限制。从IPSC得出的结论是-- 心肌细胞的机制和候选药物靶点将在较低的吞吐量下进行评估 成人心肌细胞制剂(在项目1和项目2内)和多尺度计算建模 (核心B)确认和扩展假设，从而产生与完整的相关的新见解 人类的心脏。 我们的团队，在项目和PPG内部，高度协同，特别适合执行这一任务 应该产生翻译上可操作的见解以最终改善患者状况的大型项目 管理，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.