The role of gut-heart axis in acute alcohol intoxication-induced adverse cardiovascular events

肠心轴在急性酒精中毒诱发的不良心血管事件中的作用

• 批准号: 10847617
• 负责人: Janos Paloczi
• 金额: $ 24.9万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10847617
• 关键词: Achievement; Acute; Acute myocardial infarction; Advisory Committees; Agreement; Alcohol consumption; Alcoholic Intoxication; Alcohols; Arteries; Atrial Fibrillation; Attenuated; Blood Vessels; CNR1 gene; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cardiovascular system; Circulation; Consumption; Development; Endocannabinoids; Endothelium; Endotoxemia; Endotoxins; Event; Extramural Activities; Fibroblasts; Functional disorder; Goals; Heart; Heavy Drinking; Hour; Impairment; In Vitro; Individual; Injury; Institution; Knockout Mice; Lead; Left Ventricular Function; Life; Link; Mentors; Myocardial; Myocardium; Names; National Institute on Alcohol Abuse and Alcoholism; Pattern; Peripheral; Plants; Play; Process; Production; Publications; Receptor Activation; Receptor Signaling; Research Personnel; Role; Science; Scientist; Signal Transduction; Source; Time; Training; United States; Vascular Diseases; Vascular Smooth Muscle; Vasodilation; Veins; alcohol exposure; alcohol measurement; alcohol research; analog; anandamide; antagonist; binge drinking; cardiovascular effects; cell type; cytotoxic; endocannabinoid signaling; endogenous cannabinoid system; experimental study; gut microbiome; gut microbiota; improved; in vivo; interest; intestinal barrier; member; mouse model; negative affect; novel; receptor; receptor expression; response

Project summary: Alcohol remains one of the most frequently used intoxicant in the United States especially among young individuals (1). There is ample evidence that binge alcohol consumption can lead to life-threatening adverse cardiovascular events (2,3). We have recently shown that binge alcohol drinking in a mouse model is associated with the activation of cannabinoid receptor type-1 (CB1) signaling by endocannabinoids, which plays a critical role in the development of binge alcohol intoxication-induced cardiovascular dysfunction. (Paloczi et al., accepted for publication, J Am Coll Cardiol Basic Trans Science). Activation of CB1 receptors by endocannabinoids or their plant-derived or synthetic analogs has a robust impact on cardiovascular functions, as reflected in abnormalities in cardiac inotropy, chronotropy, conduction and vascular tone (reviewed in 4,5). Therefore, elaborating the role of the gut-heart axis in the activation of the endocannabinoid system by acute alcohol intoxication may hold great translational value. The overarching aim of this proposal is to identify the cellular source of endocannabinoids and the cellular mechanisms of CB1 receptor activation in the heart and vasculature following binge alcohol drinking. To this end, I propose three specific aims: Specific aim 1: To determine the cellular source of endocannabinoids in the myocardium following alcohol exposure in vitro and potential changes in CB1 expression in various myocardial cell types. Specific aim 2: To uncover the role of gut-heart axis in binge alcohol drinking in vivo and characterize if acute alcohol-induced gut injury is involved in cardiac anandamide production that ultimately leads to alterations in left ventricular function. Specific aim 3: To investigate the impact of binge alcohol drinking-induced gut injury on vascular endocannabinoid production in vivo and the consequent vascular dysfunction. The anandamide-driven vasodilatation in different types of vessels will also be characterized ex vivo. I have been interested in the cardiovascular physiology and pathophysiology for many years. As I continue my training, I’m sure my mentor, Dr. Pal Pacher will challenge me to continuously improve as a scientist. To further facilitate the achievement of the outlined goals, Drs. Kunos, Cinar and Ungvari, three researchers with expertise in the field of my studies have agreed to be members of my advisory committee. Therefore, I am confident that with the support of my mentor, my intra-, and extramural advisory committee, and the institutional support of the NIAAA, I will be able to execute the proposed experiments, and succeed as an independent scientist in the field of cardiovascular alcohol research.

项目概述：酒精仍然是美国最常用的麻醉剂之一 尤其是年轻人（1）。有充分的证据表明酗酒 食用可导致危及生命的不良心血管事件（2，3）。我们最近 显示在小鼠模型中酗酒与激活 大麻素受体1型（CB 1）信号传导的内源性大麻素，这起着关键作用， 酗酒导致的心血管功能障碍的发展。（Paloczi等人， 接受出版，J Am科尔心脏基础跨科学）。CB 1受体的激活 内源性大麻素或其植物衍生的或合成的类似物对 心血管功能，如心脏变力性，变时性， 传导和血管张力（在4，5中综述）。因此，阐述肠心的作用 急性酒精中毒激活内源性大麻素系统的轴可能具有很大的 翻译价值这项建议的首要目标是确定细胞来源， 内源性大麻素和CB 1受体激活的细胞机制， 酗酒后的血管系统为此，我提出三个具体目标： 具体目标1：确定以下心肌中内源性大麻素的细胞来源 体外酒精暴露对不同心肌细胞CB 1表达的影响 类型具体目标2：揭示肠-心轴在体内酗酒中的作用， 表征急性酒精诱导的肠道损伤是否参与心脏花生四烯酸生产， 最终导致左心室功能的改变。具体目标3：调查影响 酗酒引起的肠道损伤对体内血管内源性大麻素产生的影响， 随之而来的血管功能障碍在不同类型的血管紧张素转换酶中， 血管也将离体表征。 多年来，我一直对心血管生理学和病理生理学感兴趣。作为 我继续我的训练，我相信我的导师，Dr. Pacher会不断挑战我， 像科学家一样进步。为了进一步促进实现所列目标，Kunos博士， 奇纳尔和昂格瓦里，三位在我的研究领域有专长的研究人员已经同意 我的顾问委员会成员因此，我相信在我导师的支持下， 我的内部和外部咨询委员会，以及NIAAA的机构支持，我将 能够执行所提出的实验，并在该领域作为独立科学家取得成功 关于心血管酒精的研究