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.

项目摘要 拟议的NHLBI K08收件人的R03小型赠款计划将使我进一步 发展成一个知名和独立的研究人员，具有阐明的专业知识 心房颤动（AF）认知能力下降的机制，使我能够理解血管 由于AF引起的血管和大脑的变化。我是心脏病学家，心脏病学家 电生理学家以及经验丰富的基础研究人员长期 目标是了解AF的电生理原因，并为 AF引起的认知和血管功能障碍的治疗。我有一个长期的，富有成效的 与我的导师的关系，经验丰富的离子频道研究员史蒂文·马克思（Steven Marx）博士，我与之 发表了一种新型的鼠标模型，表达人F1759A-NAV1.5通道的转基因小鼠 与表达反向TET-转移剂（RTTA）蛋白的小鼠交叉，该蛋白具有自发和 维持AF。我们已经证明了这些小鼠类似于患有AF的患者，会发展认知 损害。我们建议研究增加AF负担是否与血管有关 功能障碍和AF诱发的认知功能障碍是可逆的，随着AF负担的减轻。我有 安排了一个跨学科研究人员的跨学科委员会（Scott Small博士和Mu Yang博士， 哥伦比亚大学的神经生物学家），以帮助我实现（1）全面认知的目标 培训表型鼠标鼠标模型的认知障碍模型，（2）获取技能 分子心脏病学和神经生物学研究可能逆转认知功能障碍的疗法， （3）了解AF改变脑血管形成的机制。我计划使用数据 以及在此奖项中获得的技能，以开发新疗法以治疗认知功能障碍 AF并获取R01提交所需的数据。