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

针对心房颤动的基本分子机制的新的颠覆性治疗方法

基本信息

批准号：
10355010
负责人：
Rishi Arora
金额：
$ 96万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-20 至 2028-12-31
项目状态：
未结题

项目摘要

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.

项目摘要心房颤动（AF）是影响300万美国人的最常见心律障碍，是一个中风的主要原因。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，当前对AF的治疗方法 - 药物和消融 - 基于持续性AF的患者，基于优势。这被认为是因为目前的治疗没有靶向引起AF的基本分子机制。在过去的几年中，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，为AF开发机制引导治疗方法的长期目标。在Arora实验室完成的工作在过去的几年中，大型AF动物模型证明了自主神经系统信号传导，氧化损伤和CAMKII信号传导是导致电气重塑的重要机制中庭中的关键离子通道和兴奋合同耦合蛋白，从而导致建立用于阵发性AF的底物。未来几年的Arora Lab的目标是获得更好地理解阵发性AF的进展为基础的分子机制持续的AF。我们假设中庭的结构变化，例如新的副交感神经发芽，NLRP3炎性体介导的纤维化和HDAC6介导的微管介导（延迟） proteastasis）是AF进展的主要机制。我们将研究这些机制长期通过使用新型基因疗法方法在我们的过去几年的实验室。这些基因疗法方法在阻止进展方面的成功阵发性AF至持续的AF也将证明其治疗潜力。因为我们最终的目标是为持续性AF开发一种可行的临床基因治疗方法，我们最近构想了一个高度的基于新型电穿孔的方法，以促进透射基因递送。除了识别小说基因疗法针对AF的靶标，该R35提案的另一个主要目标是充分开发和优化这一点基因输送方法。 Arora实验室中提出的研究的下一阶段不仅预期给出新的机械机制对支持持久性AF的房屋肌病的创建有所了解，但也有望导致开发新的，潜在的范式转移治疗方法。