Elucidating the molecular mechanisms of cognitive decline in atrial fibrillation

项目摘要 为NHLBI K 08接受者提出的R 03小额赠款计划将使我能够进一步 发展成为一个建立和独立的研究人员与专业知识，阐明 心房颤动（AF）认知功能下降的机制，使我能够了解血管 由于AF引起的血管和大脑的变化。我是一名临床心脏病学家， 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。 治疗AF引起的认知和血管功能障碍。我有一个长期的，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，我与他 发表了一种新的小鼠模型，表达人F1759 A-NaV 1.5通道的转基因小鼠 与表达反向tet-反式激活因子（rtTA）蛋白的小鼠杂交，其表现出自发和 我们已经证明，这些小鼠，类似于AF患者， 损伤我们建议研究房颤负荷的增加是否与血管 功能障碍，并且如果AF诱发的认知功能障碍随着AF负担的减轻而可逆。我有 安排了一个多学科委员会的既定研究人员（博士斯科特小和博士穆阳， 哥伦比亚大学的神经生物学家），以帮助我实现以下目标：（1）全面认知 训练以表型化由AF引起的认知障碍的小鼠模型，（2）获得以下技能： 分子心脏病学和神经生物学来研究可能的疗法来逆转认知功能障碍， （3）了解AF改变脑血管形成的机制。我打算用数据 以及在此奖项期间获得的技能，以开发新的疗法来治疗认知功能障碍， AF并获得R 01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.