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.

项目摘要：酒精仍然是美国最常用的毒品之一 国家特别是在年轻人中（1）。有充分的证据表明酒精 消费会导致威胁生命的不良心血管事件（2,3）。我们最近有 表明在鼠标模型中饮酒与激活有关 内源性大麻素的大麻素受体类型1（CB1）信号传导，在 暴饮暴食引起的心血管功能障碍的发展。 （Paloczi等， 接受出版，J am Coll Cardiol Basic Trans Science）。通过CB1受体激活 内源性大麻素或其植物来源或合成类似物对 心血管功能，反映在心脏障碍中的异常，计时型， 传导和血管张力（在4,5中进行了综述）。因此，阐述了肠心的角色 通过急性酒精中毒激活内源性大麻素系统中的轴可能会持续很大 翻译价值。该提案的总体目的是确定细胞来源 内源性大麻素和心脏中CB1受体激活的细胞机制和 暴饮暴食后的脉管系统。为此，我提出了三个具体目标： 特定目的1：确定心肌中内源性大麻素的细胞来源 体外酒精暴露和各种心肌细胞中CB1表达的潜在变化 类型。具体目标2：揭示肠心轴在体内饮酒中饮酒中的作用 表征急性酒精引起的肠道损伤是否涉及心脏的仙人掌产生 最终导致左心室功能的改变。特定目标3：调查影响 在体内产生血管内源性大麻素的饮酒引起的肠道肠道损伤的 随之而来的血管功能障碍。不同类型的anandamide驱动的血管扩张 血管也将被特征在体内。 多年来，我对心血管生理学和病理生理学一直很感兴趣。作为 我继续训练，我确定我的心理，帕尔·帕切尔博士会挑战我继续 作为科学家的改善。为了进一步支持概述目标的实现。 Kunos， Cinar和Ungvari，三位在我的研究领域具有专业知识的研究人员已同意成为 我的咨询委员会成员。因此，我有信心在我的心理支持下 我的内部和外部咨询委员会以及NIAAA的机构支持，我将是 可以执行拟议的实验，并成为该领域的独立科学家 心血管酒精研究。