Inflammatory Bowel Disease-Induced Inflammation Potentiates Atrial Fibrillation Risk

项目摘要 心房颤动（AF）是最常见的持续性心律失常，估计影响超过4000万人 国际吧心房电生理增加（动作电位时程离散度、传导改变 速度）和结构异质性（纤维化，瘢痕）可增加AF的风险。AF的原因是 未知，但各种因素，如遗传易感性，年龄，心血管合并症， 炎症性疾病会增加其风险。溃疡性结肠炎（UC）是炎症性肠病的一种亚型， 最近被证明会增加患者患AF的风险。UC是结肠内的肠道炎症， 促进肠道生态失调的胃肠道直肠（GIT）。患有活动性结肠炎的患者有两种 房颤的风险增加，甚至在缓解期也表现出心房兴奋和收缩的变化， 重塑然而，UC增加AF风险的机制仍然不确定，并且是焦点。 of my project项目.活动性结肠炎小鼠模型中的初步数据显示迷走神经张力减弱， 毒蕈碱型乙酰胆碱受体M2（M2 R）对胆碱能信号的敏感性，以及心房肌的 传导这些变化在缓解期间是可逆的，但在慢性结肠炎模型中维持沿着 随着心脏/心房重量、心房肌细胞大小以及电生理和结构重塑的减少 的心房。基于我的试点数据，我建议测试整体假设，即UC诱导的失调， 迷走神经活动增加UC疾病进展期间AF的风险。为了验证这个假设，我将使用 活动性和慢性结肠炎的小鼠模型。目的1将研究心房肌纤维化风险的机制， 在活动性结肠炎期间，结肠活动增加。在活动性结肠炎的小鼠模型中，我将确定AF是否 发生是迷走神经信号调节异常的结果，促进了电生理学的异质性。 目的2将确定UC诱导心脏对胆碱能反应过度的机制 信号我将研究UC诱导的迷走神经张力减弱是否促进心房心肌细胞的上调， M2 R表达。目的3将研究心房颤动风险增加的机制 在慢性结肠炎期间。在慢性结肠炎的小鼠模型中，我将确定AF的发生是否是 结构异质性的增加。拟议的工作将阐明一种机制，其中房颤风险是 UC疾病进展期间增加。成功完成拟议的研究将提供一个 了解心脏，GIT和ANS之间的相互作用，并考虑到AF的一种可能机制 待定这些发现将为创造一种翻译治疗方法奠定基础。 与UC相关的疾病该研究项目将由一个特殊的赞助商团队指导， 非常适合提供完成研究，指导所需的技术的适当培训， 确保学员的短期和长期成功。建议的工作也将促进我的能力， 作为一名独立的科学家执行一个科学项目和发展。

PROJECT ABSTRACT Atrial fibrillation (AF) is the most common sustained arrhythmia that is estimated to affect over 40 million people worldwide. Increases in atrial electrophysiological (action potential duration dispersion, altered conduction velocity) and structural heterogeneity (fibrosis, scarring) can increase the risk for AF. The cause for AF is unknown, but a variety of factors such as genetic predisposition, age, cardiovascular co-morbidities, inflammatory diseases can increase its risk. Ulcerative colitis (UC), a subtype of inflammatory bowel disease, was recently shown to increase a patient’s risk for AF. UC is an intestinal inflammation within the colon and rectum of the gastrointestinal tract (GIT) that promotes gut dysbiosis. Patients with active colitis have a two-fold increased risk for AF, and even in remission exhibit changes in atrial excitation and contraction that show atrial remodeling. Yet, the mechanism with which UC increases the risk for AF remains undetermined and is the focus of my project. Preliminary data in a mouse model of active colitis show an attenuated vagal tone, increased sensitivity of the muscarinic acetylcholine receptor M2 (M2R) to cholinergic signaling, and prolonged atrial conduction. These changes are reversible during remission, but in the chronic colitis model are maintained along with a reduction in the heart/atrial weight, atrial myocyte size and electrophysiological and structural remodeling of the atria. Based on my pilot data I propose to test the overall hypothesis that UC-induced dysregulation of vagal nerve activity increases the risk for AF during UC disease progression. To test this hypothesis, I will use a mouse model of active and chronic colitis. Aim 1 will examine the mechanism by which the risk for atrial arrhythmic activity is increased during active colitis. In a mouse model of active colitis, I will determine if AF occurrence is a consequence of a dysregulation in vagal signaling, promoting electrophysiological heterogeneity. Aim 2 will determine the mechanism by which UC induces an exaggerated response of the heart to cholinergic signaling. I will examine if a UC-induced attenuated vagal tone promotes an upregulation of atrial cardiomyocyte M2R expression. Aim 3 will examine the mechanism by which the risk for atrial arrhythmic activity is increased during chronic colitis. In a mouse model of chronic colitis, I will determine if AF occurrence is a consequence of an increase in structural heterogeneity. The proposed work will elucidate a mechanism in which AF risk is increased during UC disease progression. Successful completion of the proposed research would provide an understanding of the interplay between the heart, GIT and ANS, and allow for a one possible mechanism of AF to be determined. The findings will lay the groundwork for the creation of a translational treatment for one of the diseases associated with UC. The research project will be guided by an exceptional team of sponsors that are well-suited to provide the proper training of the techniques needed to complete the research, mentorship, and to ensure short-term and long-term success of the trainee. The proposed work will also promote my ability to execute a scientific project and development as an independent scientist.