Novel Therapeutic Approaches to Atrial Fibrillation Targeting Intracellular Calci

描述（由申请人提供）：心房颤动是美国最常见的心律失常。对心律失常分子机制的不完全理解阻碍了更有效的新型抗心律失常药物的开发。我们的研究重点是研究房颤的分子机制，特别是细胞内钙释放通道功能障碍。了解心脏钙通道是如何被调节的，以及新的药物化合物是如何使这些通道功能正常化的，这可能会改善房颤的治疗策略。尽管人们强烈关注房颤的分子机制，并努力开发更有效和更安全的药物治疗来预防房颤，但更好地了解房颤机制和改进治疗方法的必要性已被广泛接受。一个新兴的调查线已经改变钙（Ca2+）稳态和房颤的起始和延续之间的联系。希望更好地了解Ca2+稳态改变在房颤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。申请人建议在房颤动物模型中确定心房和肺静脉肌细胞中RyR2通道泄漏的机制，并测试一种由申请人实验室开发的新药S107（一种rycal），该药物与RyR2通道结合，防止钙稳定蛋白2从通道中耗竭，从而抑制病理性舒张期SR Ca2+泄漏。A rycal目前正处于治疗心力衰竭和心源性猝死的II期临床研究中，并将用于房颤患者的试验。

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.