New and Disruptive Therapeutic Approaches to Target Fundamental Molecular Mechanisms Underlying Atrial Fibrillation

项目摘要 心房颤动（AF）是最常见的心律失常，影响超过300万美国人，是一种严重的心脏病。 中风的主要原因由于AF主要是一种与年龄相关的疾病，因此它正在迅速成为一种流行病， 人口老龄化不幸的是，目前的房颤治疗方法--包括药物和消融-- 在持续性房颤患者中， 针对导致AF的基本分子机制。在过去的几年里，Arora实验室在 西北大学一直在努力更好地了解AF的分子机制， 长期目标是开发一种机制指导的AF治疗方法。在Arora实验室完成的工作 在过去几年中，在AF的大型动物模型中已经证明，自主神经系统 信号传导、氧化损伤和CAMKII信号传导是导致电重构的重要机制。 关键离子通道和兴奋收缩偶联蛋白，从而导致 Arora实验室在未来几年的目标是获得 更好地了解阵发性AF进展的分子机制， 我们假设心房的结构变化，如新的副交感神经， 出芽、NLRP 3炎性体介导的纤维化和HDAC 6介导的微管破裂（脱轨 蛋白酶抑制）是AF进展的关键机制。我们将在 通过使用我们开发的新型基因治疗方法， 实验室在过去的几年里这些基因治疗方法在阻止肿瘤进展方面的成功 阵发性AF到持续性AF也将证明其治疗潜力。因为我们的最终目标是 开发一种临床上可行的持续性AF基因治疗方法，我们最近设想了一种高度 新的基于电穿孔的方法，以促进经静脉基因输送。除了确定新的 作为AF的基因治疗靶点，R35提案的另一个主要目标将是充分开发和优化这一点。 基因递送方法。 阿罗拉实验室提出的下一阶段研究不仅有望提供新的机制， 对支持持续性AF的心房肌病的创建的见解，但也有望导致 开发新的、可能改变范式的AF治疗方法。

PROJECT SUMMARY Atrial fibrillation (AF) is the most common heart rhythm disorder that affects >3 million Americans and is a major cause of stroke. Since AF is primarily an age-related disease, it is fast becoming an epidemic in a rapidly aging population. Unfortunately, current therapeutic approaches to AF – both pharmacological and ablation- based - are sub-optimal in patients with persistent AF. This is thought to be because current treatments do not target the fundamental, molecular mechanisms that cause AF. Over the last several years, the Arora lab at Northwestern University has worked hard to better understand the molecular mechanisms underlying AF, with the long term goal of developing a mechanism-guided therapeutic approach to AF. Work done in the Arora lab over the last several years in large animal models of AF has demonstrated that autonomic nervous system signaling, oxidative injury and CAMKII signaling are important mechanisms leading to electrical remodeling of key ion channels and excitation contraction coupling proteins in the atrium, thereby leading to the establishment of substrate for paroxysmal AF. The goal of the Arora lab over the next several years is to obtain a better understanding of the molecular mechanisms that underlie the progression of paroxysmal AF to persistent AF. We postulate that structural changes in the atrium such as new parasympathetic nerve sprouting, NLRP3 inflammasome mediated fibrosis and HDAC6 mediated breakdown of microtubules (derailed proteastasis) are key mechanisms underlying this progression of AF. We will study these mechanisms in chronically tachypaced large animal models of AF by using novel gene therapy approaches developed in our lab over the last several years. Success of these gene therapy approaches in arresting progression of paroxysmal AF to persistent AF will also demonstrate their therapeutic potential. Since our eventual goal is to develop a clinically viable gene therapy approach for persistent AF, we have recently conceived of a highly novel electroporation-based approach to facilitate trans-venous gene delivery. In addition to identifying novel gene therapy targets for AF, another major goal of this R35 proposal will be to fully develop and optimize this gene delivery approach. The next phase of the research proposed in the Arora lab is not only expected to give fresh mechanistic insights into the creation of an atrial myopathy that supports persistent AF, but is also expected to led to the development of new, potentially paradigm-shifting therapeutic approaches to AF.