Novel Therapeutic Approaches to Atrial Fibrillation Targeting Intracellular Calci

描述（由申请人提供）：房颤是美国最常见的心律失常。由于对这些心律失常的分子机制的不完全理解，更有效的新型抗心律失常药物的开发受到阻碍。我们的研究项目集中在研究房颤的分子机制，特别是细胞内钙释放通道功能障碍的作用。了解心脏中的钙通道是如何调节的，以及新的药理学化合物如何使这些通道的功能障碍正常化，可能会导致改善AF的治疗策略。尽管人们非常关注了解导致AF的分子机制，并努力开发更有效、更安全的药物治疗来预防AF，但人们广泛接受了更好地了解AF机制和改善治疗的需要。一个新兴的调查线已改变钙（Ca2+）稳态和AF的启动和永久之间的联系。希望更好地理解改变的Ca2+稳态在AF的发生和维持中的作用，可以导致开发新的，更有效和更安全的药物治疗。申请人提出确定AF动物模型中心房和肺静脉肌细胞中渗漏RyR2通道的潜在机制，并测试在申请人实验室开发的新型药物S107（rycal），其结合RyR2通道并防止钙稳定蛋白2从通道耗尽，从而抑制病理性舒张SR Ca2+渗漏。一种rycal目前正处于心力衰竭和心源性猝死的II期临床研究中，并将可用于房颤患者的测试。 公共卫生相关性：心房颤动（AF）是最常见的心律失常，主要由于卒中和心血管事件导致大量发病率和死亡率。人们一直非常关注了解导致AF的分子机制，并努力开发更有效和更安全的药物治疗来预防AF。然而，更好地了解AF机制和改进治疗的必要性已被广泛接受。一个新兴的研究方向是探索钙（Ca2+）稳态改变的作用，这是与AF引发的局灶性活动和AF永久化（由于快速激发病灶和折返）相关的关键因素。希望更好地理解改变的Ca2+稳态在AF的发生和维持中的作用，可以导致开发新的，更有效和更安全的药物治疗。拟议研究的目标是使用新的AF动物模型来研究AF中扰乱Ca2+稳态的分子机制。这些相同的AF新模型将用于确定修复RyR2通道泄漏的新型化合物的疗效，并可能成为AF新疗法的候选者。

DESCRIPTION (provided by applicant): Atrial fibrillation is the most common arrhythmia in the United States. The development of more effective new anti-arrhythmic drugs has been hampered by an incomplete understanding of the molecular mechanisms underlying these arrhythmias. Our research project focuses on studying the molecular mechanisms underlying AF, in particular the role of intracellular calcium-release channel dysfunction. Understanding how calcium channels in the heart are regulated and how new pharmacological compounds may normalize dysfunction of these channels may lead to improved therapeutic strategies for AF. Despite intense focus on understanding the molecular mechanisms that cause AF, and efforts to develop more effective and safer drug therapies to prevent AF, the need for better understanding of AF mechanisms and improved therapy is widely accepted. An emerging line of investigation has been the link between altered calcium (Ca2+) homeostasis and AF-initiation and perpetuation. It is hoped that a better understanding of the role of altered Ca2+ homeostasis in the genesis and maintenance of AF could lead to the development of novel, more effective and safer drug therapies. The applicant proposes to determine the mechanism underlying leaky RyR2 channels in atrial and pulmonary vein myocytes in animal models of AF, and test a novel drug S107 (a rycal), developed in the applicant's laboratory, that binds to RyR2 channels and prevents depletion of calstabin2 from the channel thereby inhibiting pathologic diastolic SR Ca2+ leak. A rycal is now in Phase II clinical studies for heart failure and sudden cardiac death and would be available for testing in AF patients. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity and mortality primarily due to stroke and cardiovascular events. There has been intense focus on understanding the molecular mechanisms that cause AF, and efforts to develop more effective and safer drug therapies to prevent AF. Nevertheless, the need for better understanding of AF mechanisms and improved therapy is widely accepted. An emerging line of investigation has been exploration of the role of altered calcium (Ca2+) homeostasis as a key element linked to AF-initiating focal activity and AF perpetuation due to rapid firing of foci and reentry. It is hoped that a better understanding of the role of altered Ca2+ homeostasis in the genesis and maintenance of AF could lead to the development of novel, more effective and safer drug therapies. The goal of the proposed studies is to use novel animal models of AF to study the molecular mechanisms that perturb Ca2+ homeostasis in AF. These same novel models of AF will be used to determine the efficacy of novel compounds that fix the leak in RyR2 channels and may be candidates for new therapeutics for AF.