Role of arginine-vasopressin and V1A receptor in psychosocial stress-induced myocardial injury

项目概要/摘要 在美国，心脏病是导致死亡的主要原因， 疾病占美国总死亡人数的28%以上。急性心脏事件（例如，心肌 心肌梗塞、应激性心肌病和心源性猝死）由于其不可预测性而备受关注 以及缺乏有关致病机制的知识。社会心理压力源（例如，焦虑、人格 特征、社会隔离）使心血管系统负担过重，是心血管事件的危险因素， 中风在心理社会压力的背景下描述心脑互动是一个重要的第一步 确定与疾病风险增加相关的基因-环境相互作用的步骤。研究人员 提出情绪和心理压力可能导致交感神经-儿茶酚胺能激增， 降低肌细胞活力和/或心脏功能。下丘脑加压素（AVP）和V1 A 血管紧张素Ⅱ受体（V1 AR）与AVP一样，对心理社会应激相关的心脏病具有巨大的治疗潜力 其受体通过调节神经内分泌应激反应促进健康和生存。论文的主要 AVP通过V1 AR起作用，通过动态调节V1 AR来促进健康和福祉。 腹侧被盖区（VTA）对应激的神经反应。AVP与压力相关的疾病有关， 人类和动物的情绪反应改变，可以通过抗精神病药物治疗调节， 提示在应激相关反应中存在AVP-VTA相互作用。然而，神经机制， 是AVP、Avpr 1a基因表达、VTA依赖性应激反应和 心血管功能尚未完全确定。为了弥补这一知识差距，主要目标是 这项建议的目的是研究神经肽AVP的心脏保护特性， 确定Avpr 1a基因表达、儿茶酚胺 释放，和心脏病的结果在心理社会应激诱导的心肌损伤动物模型。 许多易感个体暴露于多种风险因素，这些因素往往相互作用， 心血管疾病风险。使用叙利亚仓鼠，我计划调查两个 社会心理风险因素、社会孤立和攻击性。目的1将检验VTA中AVP 阻断应激诱导的儿茶酚胺释放和心肌缺血-再灌注损伤的恶化， 目的2将检验V1 AR基因表达模式将预测对应激和AVP的反应的假设， 治疗心脏损伤和儿茶酚胺。学员还将参加职业发展活动： 学习如何进行心肌缺血再灌注损伤手术和进行基因表达研究; 参加正式的职业发展计划;参加心血管遗传学的特别计划 和流行病学;完成科学课程，以获得新的知识;通过接受 从经验丰富的研究人员的指导;并建立一个成功的独立的研究计划。

PROJECT SUMMARY/ABSTRACT Heart disease is the leading cause of death in the United States and together with cerebrovascular diseases account for over 28% of total deaths in the United States. Acute cardiac events (e.g., myocardial infarction, stress cardiomyopathy, and sudden cardiac death) are concerning because of their unpredictability and the lack of knowledge regarding causative mechanisms. Psychosocial stressors (e.g., anxiety, personality traits, social isolation) overburden the cardiovascular system and are risk factors for cardiovascular events and stroke. Characterization of heart-brain interactions in the context of psychosocial stress is an important first step in identifying gene-environment interactions that are associated with increased disease risk. Researchers have proposed that emotional and psychosocial stress may lead to a sympathetic-catecholaminergic surge that decreases myocyte viability and/or cardiac function. Hypothalamic arginine-vasopressin (AVP) and the V1A receptor (V1AR) have great therapeutic potential for psychosocial stress-associated heart disease, as AVP and its receptors promote health and survival by regulating neuroendocrine stress responses. The main thesis of this proposal is that AVP, acting via the V1AR, promotes health and wellbeing by dynamically modulating neural responses in the ventral tegmental area (VTA) to stressors. AVP is linked to stress-related disorders in humans and altered emotional reactivity in animals, that can be modulated by antipsychotic treatment, suggesting an AVP-VTA interaction in stress-associated responses. However, the neural mechanisms that underlie the relationships among AVP, Avpr1a gene expression, VTA-dependent stress responses, and cardiovascular function have not been fully characterized. To address this gap in knowledge, the major goals of this proposal are to investigate the cardioprotective properties of the neuropeptide AVP and determine whether there is an association between the Avpr1a gene expression, catecholamine release, and heart disease outcomes in a psychosocial stress-induced myocardial injury animal model. Many susceptible individuals are exposed to multiple risk factors that often interact with each other, magnifying cardiovascular disease risk. Using the Syrian hamster, I plan to investigate the interaction between two psychosocial risk factors, social isolation and aggression. Aim 1 will test the hypothesis that AVP in the VTA blocks stress-induced catecholamine release and exacerbation of myocardial ischemia-reperfusion injury, and aim 2 will test the hypothesis that V1AR gene expression patterns will predict response to stress and AVP- treatment on heart injury and catecholamines. The trainee will also participate in career development activities: learn how to perform myocardial ischemia-reperfusion injury surgeries and conduct gene expression studies; participate in a formal career development program; participate in a special program in cardiovascular genetics and epidemiology; complete scientific courses to gain new knowledge; improve grant writing skills by receiving mentorship from experienced investigators; and establish a successful independent research program.