Novel Therapeutic Approaches to Atrial Fibrillation Targeting Intracellular Calci

描述(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了解不完全，更有效的抗心律失常新药的开发一直受到阻碍。我们的研究项目集中于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，以及新的药物化合物如何使这些通道的功能正常，可能会导致改进对房颤的治疗策略。尽管人们高度重视了解房颤的分子机制，并努力开发更有效、更安全的药物疗法来预防房颤，但人们普遍认为有必要更好地了解房颤的机制和改进治疗方法。一个新的研究方向是改变钙(Ca~(2+))稳态与房颤的启动和持续之间的联系。希望更好地了解钙离子稳态在房颤发生和维持中的作用，有助于开发新的、更有效和更安全的药物治疗方法。申请人建议在房颤动物模型中确定心房和肺静脉肌细胞RyR2通道泄漏的机制，并测试在申请人实验室开发的新药S107(A Rycal)，该新药与RyR2通道结合并防止通道中的Calstain2耗尽，从而抑制病理性舒张期SR钙离子泄漏。阿雷卡目前处于心力衰竭和心脏性猝死的第二阶段临床研究，将可用于房颤患者的测试。 公共卫生相关性：房颤(AF)是最常见的心律失常，主要由中风和心血管事件导致的发病率和死亡率很高。人们一直关注于了解引起房颤的分子机制，并努力开发更有效、更安全的药物疗法来预防房颤。然而，更好地了解房颤的机制和改进治疗的必要性被广泛接受。一个新的研究方向是探索改变的钙(Ca~(2+))稳态作为一个关键因素与房颤启动局灶性活动和由于病灶的快速激发和折返而持续房颤的关键因素的作用。希望更好地了解钙离子稳态在房颤发生和维持中的作用，有助于开发新的、更有效和更安全的药物治疗方法。这项研究的目的是利用新的房颤动物模型来研究房颤中扰乱钙稳态的分子机制。这些相同的房颤新模型将用于确定修复RyR2通道泄漏的新化合物的疗效，并可能成为治疗房颤的新疗法的候选药物。

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.