Virtual drug screen reveals context-dependent inhibition of cardiomyocyte hypertrophy

建议书摘要 心力衰竭是世界范围内主要的死亡原因。心肌细胞肥大是心脏的主要预测指标 失败，因为它有助于心脏的不适应重塑。因此肥大是一种很好的治疗方法。 预防心力衰竭发作的目标。肥大是由复杂的细胞内信号介导的， 这限制了我们对心肌细胞中药物活性进行有效建模的能力。目前还没有治疗方法 针对心肌细胞肥大的细胞内信号转导。之前的工作，由 Saucerman实验室利用信号网络的计算模型来模拟心肌细胞在 肥大的背景。这些模拟使我们能够探索药物如何抑制心肌细胞 使用系统生物学方法进行肥大。识别针对心肌细胞肥大的药物将 允许翻译应用。这项拨款的中心重点是确定抑制心肌细胞的药物。 肥大及其作用机制。目标1将使用心肌细胞的计算模型 肥大信号用于筛选FDA批准的抑制肥厚药物并验证这些预测 试验性的。目标2将使用蛋白质相互作用数据来确定假定的抗肥厚机制 药物从单独的体外药物筛选。这些目标加在一起将导致药物的选择和测试 用于抑制心肌细胞肥大，并将为设计虚拟药物奠定平台 筛查心脏病。

Proposal Abstract Heart failure is a leading cause of death worldwide. Cardiomyocyte hypertrophy is a leading predictor of heart failure as it contributes to maladaptive remodeling of the heart. Hypertrophy is therefore a good therapeutic target for preventing the onset of heart failure. Hypertrophy is mediated by complex intracellular signaling, which limits our ability to effectively model drug activity in cardiomyocytes. Currently there are no therapeutics that specifically target the intracellular signaling of cardiomyocyte hypertrophy. Previous work by the Saucerman lab has utilized computational models of signaling networks to simulate cardiomyocyte behavior in the context of hypertrophy. These simulations allow us to explore how drugs may inhibit cardiomyocyte hypertrophy using a systems biology approach. Identifying drugs that target cardiomyocyte hypertrophy would allow for translational application. The central focus of this grant is to identify drugs that inhibit cardiomyocyte hypertrophy and the mechanisms by which they act. Aim 1 will use a computational model of cardiomyocyte hypertrophy signaling to screen FDA approved drugs that inhibit hypertrophy and validate these predictions experimentally. Aim 2 will use protein interaction data to identify the mechanisms of putative antihypertrophic drugs from a separate in vitro drug screen. These aims together will result in the selection and testing of drugs repurposed for the inhibition of cardiomyocyte hypertrophy, and will lay the platform for designing virtual drug screens for heart disease.