家族性扩张型心肌病(DCM)通常由参与多种细胞过程的基因中的常染色体显性点突变引起。包括肌节收缩。虽然患者研究已经定义了DCM的遗传景观,遗传学目前不用于病人护理,患者接受类似的治疗,无论潜在的突变。有人提出,基于潜在突变的分子机制的精准医学方法可以改善结果;然而,由于难以将基因型和表型联系起来,然后利用这些信息来确定治疗方法,因此实现这种方法具有挑战性。这里,我们使用多尺度实验和计算方法来测试是否可以利用分子机制知识来连接基因型,表型,和肌钙蛋白TDCM突变的药物反应,删除K210。以前,我们证明了在分子尺度上,这种突变减少了细丝的激活。这里,我们使用这种分子缺陷的计算模型来预测突变体会降低细胞和组织的收缩性,我们在人心肌细胞和工程心脏组织中验证了这一预测。然后,我们使用我们对分子机制的知识来计算模拟可以激活细丝的小分子的影响。我们通过实验证明,该模型正确地预测了小分子可以以舒张功能为代价部分挽救收缩功能障碍。一起来看,我们的结果证明了如何利用分子机制来连接基因型和表型,并激发策略来优化DCM的基于机制的治疗方法.
■扩张型心肌病(DCM),心力衰竭的主要原因,其特征是心脏无法在正常的充盈压力下灌注身体。DCM有多种原因,包括肌节蛋白的点突变,但是大多数患者接受类似的治疗,无论DCM的根本原因是什么。许多患者仍然得不到目前的治疗,需要新的方法。这里,我们使用多尺度实验和计算方法来证明如何利用分子机制知识来准确预测患者特异性突变的影响和对推定疗法的反应。我们的方法为DCM的精准医学方法奠定了基础。
Familial dilated cardiomyopathy (DCM) is frequently caused by autosomal dominant point mutations in genes involved in diverse cellular processes, including sarcomeric contraction. While patient studies have defined the genetic landscape of DCM, genetics are not currently used in patient care, and patients receive similar treatments regardless of the underlying mutation. It has been suggested that a precision medicine approach based on the molecular mechanism of the underlying mutation could improve outcomes; however, realizing this approach has been challenging due to difficulties linking genotype and phenotype and then leveraging this information to identify therapeutic approaches. Here, we used multiscale experimental and computational approaches to test whether knowledge of molecular mechanism could be harnessed to connect genotype, phenotype, and drug response for a DCM mutation in troponin T, deletion of K210. Previously, we showed that at the molecular scale, the mutation reduces thin filament activation. Here, we used computational modeling of this molecular defect to predict that the mutant will reduce cellular and tissue contractility, and we validated this prediction in human cardiomyocytes and engineered heart tissues. We then used our knowledge of molecular mechanism to computationally model the effects of a small molecule that can activate the thin filament. We demonstrate experimentally that the modeling correctly predicts that the small molecule can partially rescue systolic dysfunction at the expense of diastolic function. Taken together, our results demonstrate how molecular mechanism can be harnessed to connect genotype and phenotype and inspire strategies to optimize mechanism-based therapeutics for DCM.