Elucidating the molecular mechanisms of cognitive decline in atrial fibrillation

项目总结 为NHLBI K08获奖者建议的R03小额助学金计划将使我的 发展成为成熟和独立的研究人员，具有阐明 房颤认知功能减退的机制及对血管的认识 房颤引起的血管和大脑的变化。我是一名临床心脏病专家，心脏病 电生理学家，以及经验丰富的基础和翻译研究人员，其长期 目的是了解房颤的电生理原因，并开发新的治疗方法。 房颤引起的认知和血管功能障碍的治疗。我有一个历史悠久的，富有成效的 与我的导师史蒂文·马克思博士的关系，他是一位经验丰富的离子通道研究员，我和他 发表了一种新的小鼠模型，表达人F1759A-NaV1.5通道的转基因小鼠 与表达逆转录反式激活因子(RTTA)蛋白的小鼠杂交，表现出自发和 持续房颤。我们已经证明了这些小鼠，类似于房颤患者，发展了认知能力 减损。我们建议研究房颤负荷增加是否与血管有关 功能障碍和房颤引起的认知功能障碍随着房颤负荷的减轻是可逆的。我有过 安排了一个由知名调查人员组成的多学科委员会(Scott Small博士和Mu Yang博士， 哥伦比亚大学的神经生物学家)，帮助我实现(1)综合认知的目标 对房颤引起的认知障碍小鼠模型进行表型训练，(2)获得 分子心脏病学和神经生物学研究逆转认知功能障碍的可能疗法， 以及(3)了解房颤改变脑血管形成的机制。我计划使用数据 以及在该奖项期间获得的技能，以开发新的治疗方法来治疗由于 并获得R01提交所需的数据。

PROJECT SUMMARY The proposed R03 Small Grant Program for NHLBI K08 Recipients will enable my further development into an established and independent researcher with expertise on elucidating the mechanisms of cognitive decline in atrial fibrillation (AF) and enable me to understand the vascular changes in the blood vessels and brain due to AF. I am a clinical cardiologist, cardiac electrophysiologist, as well as an experienced basic and translational researcher whose long-term goal is to understand the electrophysiologic causes of AF and to develop new therapies for the treatment of cognitive and vascular dysfunction due to AF. I have a long-standing, productive relationship with my mentor, Dr. Steven Marx, an experienced ion channel researcher, with whom I published a novel mouse model, transgenic mice expressing human F1759A-NaV1.5 channels crossed with mice expressing reverse tet-transactivator (rtTA) protein, which exhibit spontaneous and sustained AF. We have demonstrated that these mice, akin to patients with AF, develop cognitive impairment. We propose to study whether increasing AF burden is associated with vascular dysfunction and if AF induced cognitive dysfunction is reversible with reduction of AF burden. I have arranged a multidisciplinary board of established investigators (Dr. Scott Small and Dr. Mu Yang, neurobiologists at Columbia University), to help me attain the goals of (1) comprehensive cognitive training to phenotype a mouse model of cognitive impairment due to AF, (2) acquiring skills in molecular cardiology and neurobiology to study possible therapies to reverse cognitive dysfunction, and (3) understanding the mechanisms in which AF alters brain vascularization. I plan to use data and skills acquired during this award to develop new therapies to treat cognitive dysfunction due to AF and obtain the data necessary for an R01 submission.