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

项目概要 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 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——药物和消融—— 基于 - 对于持续性 AF 患者来说效果不佳。这被认为是因为目前的治疗方法不能 针对导致 AF 的基本分子机制。在过去的几年里，阿罗拉实验室 西北大学一直致力于更好地了解 AF 的分子机制， 开发机制引导的 AF 治疗方法的长期目标。在 Arora 实验室完成的工作 过去几年在大型 AF 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塑的重要机制 心房中的关键离子通道和兴奋收缩耦合蛋白，从而导致 阵发性房颤基质的建立。阿罗拉实验室未来几年的目标是获得 更好地了解阵发性 AF 进展为潜在的分子机制 持续自动对焦。我们假设心房的结构变化，例如新的副交感神经 发芽、NLRP3 炎症小体介导的纤维化和 HDAC6 介导的微管破裂（脱轨） 蛋白酶抑制）是 AF 进展的关键机制。我们将研究这些机制 通过使用我们开发的新型基因治疗方法，建立慢性快速节奏的大型 AF 动物模型 过去几年的实验室。这些基因治疗方法在阻止疾病进展方面取得了成功 阵发性 AF 到持续性 AF 也将展示其治疗潜力。因为我们的最终目标是 为了开发一种临床上可行的持续性房颤基因治疗方法，我们最近构想了一种高度 基于电穿孔的新型方法促进经静脉基因递送。除了识别小说 AF 的基因治疗目标，该 R35 提案的另一个主要目标将是充分开发和优化这一目标 基因传递方法。 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 对创建支持持续性房颤的心房肌病的见解，但也有望导致 开发新的、潜在的范式转变的 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.