Closing the therapeutic loop
Closing the therapeutic loop
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DOI：
10.1016/j.abb.2019.01.006
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发表时间：
2019-03-15
影响因子：
3.9
通讯作者：
Wenk, Jonathan F.
中科院分区：
文献类型：
--
作者：
Campbell, Kenneth S.;Yengo, Christopher M.;Wenk, Jonathan F.
我们的一位临床同事曾经告诉我们，“有博士的问题，有重要的问题。你应该研究重要的问题。”我们不接受这位同事对基础科学的直言不讳的批评，但我们认识到，随着领域的发展，研究人员可以做更多的工作来增加他们工作的实际影响。在我们看来，心肌收缩的领域已经达到了这一点。数千名科学家数十年的工作为我们提供了有关驱动和调节心室功能的分子，细胞和组织水平机制的详细信息。在我们看来，现在是研究人员更加重视利用这些知识来改善患者护理的时候了。本文概述了一个潜在的方法的基础上多尺度计算机建模的心脏功能。我们的愿景是建立一个跨学科团队，通过使用整合基因组学、蛋白质组学、成像和功能数据的个性化计算机模型预测心脏对每种潜在治疗方案的反应，优化心脏病患者的治疗计划。在接下来的几年里，我们希望通过计划一项临床试验来实现这一登月目标，该试验旨在测试实施模型预测疗法是否比当前的护理标准更能帮助患者。我们的领域现在了解到，收缩力是由肌球蛋白头和肌动蛋白上的结合位点之间的相互作用产生的[1]。驱动跨桥循环的能量来自ATP分子的水解，我们对肌球蛋白的机械化学的许多方面有详细的了解[2]。我们还了解到，细胞内Ca 2+浓度通过涉及肌钙蛋白和原肌球蛋白的复杂机制控制收缩活动[3]。这些过程是协同的，因此一个结合位点的状态取决于其邻居的状态[4]。粗肌丝也是动态的，肌球蛋白头在OFF和ON状态之间转换的速率可能取决于力[5-7]。
One of our clinical colleagues once told us,“There are PhD problems, and there are important problems. You should work on important problems.” We reject our colleague’s blunt criticism of basic science but we recognize that, as fields advance, researchers can do more to increase the tangible impact of their work. It seems to us that the field of myocardial contraction has reached this point. Decades of work by thousands of scientists has provided us with detailed information about the molecular, cellular, and tissue-level mechanisms that drive and regulate ventricular function. In our opinion, it is time for researchers to put more emphasis on leveraging that knowledge to improve patient care. This article outlines one potential approach based on multiscale computer modeling of cardiac function. Our vision is a transdisciplinary team that optimizes treatment plans for patients who have cardiac disease by predicting how the heart will respond to each of the potential therapeutic options using personalized computer models that integrate genomic, proteomic, imaging, and functional data. Over the next few years, we want to work towards that moonshot goal by planning a clinical trial that tests whether implementing model-predicted therapies helps patients more than the current standard of care.Reductionist techniques have dominated myofilament research for the last 70 years. Our field now understands that contractile force is generated by interactions between myosin heads and binding sites on actin [1]. The energy that drives cross-bridge cycling comes from the hydrolysis of ATP molecules and we have detailed knowledge about many aspects of myosin’s mechano-chemistry [2]. We have also learned that the intracellular Ca2+ concentration controls contractile activity through complex mechanisms involving troponin and tropomyosin [3]. These processes are cooperative so the status of one binding site depends on the status of its neighbors [4]. Thick filaments are also dynamic with myosin heads transitioning between OFF and ON states at rates that are likely to depend on force [5-7].