Pharmacogenomics and antiarrhythmic therapy: An in silico investigation

描述(由申请人提供)：心律失常的药物治疗是一个长期寻求但仍难以实现的目标。用药物治疗心律失常的疗效和结果很差，部分原因是未能准确预测具有隐含复杂药效学的药物如何影响多组分相互作用的心肌细胞和组织。例如，将心脏离子通道的药物阻断表示为减小的电流幅度过于简单化，无法预测药物效应。相反，必须考虑多种因素，包括复杂的药物药代动力学、pH依赖、电压依赖、药物的构象特异性阻断和速率依赖特性，以及药物与心律失常的多种机制和触发因素的相互作用，以开发适当的药物干预来治疗心律失常。在过去的十年里，这些问题变得更加复杂，在此期间，遗传进展揭示了基因在决定心律失常的易感性和药物治疗的有效性方面也发挥了作用。因此，现在清楚的是，除了药效学之外，在心律失常的药物治疗中，必须考虑基因型因素。我们的目标是通过在虚拟心肌细胞和组织中构建药物阻断的详细数学路径来发展新的理论方法，以弥合这一差距。我们研究的长期目标是建立一个准确预测药物与心脏离子通道相互作用的框架，特别是预测突变和药物阻断对细胞和组织水平电行为的紧急影响。我们将致力于以下三个具体目标：1：建立一个模拟心肌钠通道药物阻滞剂的理论框架--一个包括钠通道阻滞剂的pH依赖性分配、膜扩散、相互作用的构象-状态特异性和电压依赖性的综合模型。2：目的2：利用虚拟心肌细胞的理论框架，研究正常或心律失常连锁突变钠通道的钠通道阻断对细胞活动的影响。3：使用组织水平模拟测试药物基因组学、药物治疗和心律失常之间的关系。这一提议的优点在于测试和预测旨在诊断和治疗心律失常的药物干预结果的方法的新颖性，并代表着朝着虚拟药物测试系统的进展。

DESCRIPTION (provided by applicant): Pharmacological treatment of cardiac arrhythmia is a long sought and as yet elusive goal. Poor efficacy and outcomes in treating arrhythmia with drugs is due, in part, to failure to accurately predict how drugs with implicitly complex pharmacodynamics affect multi-component interactive cardiac cells and tissues. For example, a representation of drug block of cardiac ion channels as reduced current amplitude is overly simplistic and fails to predict drug effects. Rather, multiple factors including complex drug pharmacokinetics, pH dependence, voltage dependence, conformation-specific block and rate-dependent properties of drugs, as well drug interaction with the multiple mechanisms and triggers of arrhythmia must be considered for development of appropriate pharmacological intervention for arrhythmia management. These issues have been further complicated in the last decade, during which genetic advances have revealed that genes also play a role in determining arrhythmia susceptibility and effectiveness of drug treatment. As a result, it is now clear that, in addition to pharmacodynamics, genotype must be considered as a factor in pharmacological management of arrhythmia. Our goal is to develop novel theoretical approaches through the construction of detailed mathematical pathways of drug block in virtual cardiac cells and tissues to bridge this gap. The long-term purpose of our studies is to develop a framework for accurate prediction of drug interaction with cardiac ion channels, and especially, to predict the emergent effects of mutations and drug block on cellular and tissue level electrical behavior. We will address the following three specific aims: 1: To develop a theoretical framework to simulate pharmacological block of cardiac Na+- channels - A comprehensive model that includes pH dependent partitioning, membrane diffusion, conformation-state specificity of interaction and voltage dependence of Na+ channel block. 2: AIM 2: To utilize the theoretical framework in virtual cardiac cells to examine the effects of Na+ channel block of normal or arrhythmia linked mutant Na+ channels on cell activity. 3: To test, using tissue level simulations, the relationship between pharmacogenomics, drug treatment and arrhythmia. The merit of this proposal lies in the novelty of the approach to test and predict the outcomes of drug interventions intended for diagnosis and treatment of cardiac arrhythmia and represents progress towards a virtual drug testing system.