Elucidating the molecular mechanisms of cognitive decline in atrial fibrillation

阐明房颤认知能力下降的分子机制

• 批准号: 9915970
• 负责人: Elaine Y Wan
• 金额: $ 8.1万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915970
• 关键词: Acute; Age; Age-Months; Animal Model; Animals; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Attenuated; Award; Biochemical; Blood Vessels; Brain; Cardiac; Cardiology; Cardiovascular system; Cerebrospinal Fluid; Clinical; Data; Dementia; Development; Disease; Doxycycline; Electrophysiology (science); Exhibits; Female; Fibrosis; Fostering; Functional disorder; Gender; Genes; Genetic; Goals; Grant; Heart Atrium; Human; Impaired cognition; Infarction; Ion Channel; Learning; Link; Long-Term Potentiation; Magnetic Resonance Imaging; Mentors; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Mutation; National Heart, Lung, and Blood Institute; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurologic; Patients; Phenotype; Prevalence; Process; Proteins; Publishing; Reactive Oxygen Species; Recording of previous events; Research Personnel; Risk Factors; Stroke; Structural defect; Testing; Tetanus Helper Peptide; Thromboembolism; Time; Trans-Activators; Transgenic Mice; Universities; Vascular Diseases; Vascularization; Yang; base; brain tissue; cognitive development; cognitive function; cognitive testing; cognitive training; experience; field study; gain of function; indexing; insight; male; morris water maze; mortality; mouse model; multidisciplinary; neurovascular; novel; novel therapeutics; object recognition; prevent; programs; ranolazine; skills; touchscreen; translational scientist; vascular bed

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.

项目概要 拟议的针对 NHLBI K08 受助者的 R03 小额赠款计划将使我能够进一步 发展成为一名成熟的独立研究人员，具有阐明问题的专业知识 心房颤动 (AF) 认知能力下降的机制，使我能够了解血管 AF 导致血管和大脑发生变化。我是一名临床心脏病专家，心脏 电生理学家，以及经验丰富的基础和转化研究员，其长期 目标是了解 AF 的电生理原因并开发新的治疗方法 治疗房颤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 Steven Marx 博士的关系，他是一位经验丰富的离子通道研究员，我与他的关系 发表了一种新型小鼠模型，表达人类F1759A-NaV1.5通道的转基因小鼠 与表达逆向 tet 反式激活蛋白 (rtTA) 蛋白的小鼠杂交，该蛋白表现出自发性和 持续自动对焦。我们已经证明，这些小鼠与 AF 患者类似，能够发展出认知能力 损害。我们建议研究房颤负担增加是否与血管性相关 房颤引起的认知功能障碍是否可以通过房颤负担的减轻而逆转。我有 安排了一个由资深研究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 训练对因 AF 导致的认知障碍的小鼠模型进行表型分析，(2) 获得以下方面的技能： 分子心脏病学和神经生物学研究扭转认知功能障碍的可能疗法， (3) 了解房颤改变脑血管化的机制。我打算使用数据 以及在该奖项期间获得的技能，用于开发治疗认知功能障碍的新疗法 AF 并获取 R01 提交所需的数据。