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

项目摘要/摘要 心脏病是美国的主要死亡原因，与脑血管疾病一起 在美国，疾病占总死亡人数的28%以上。急性心脏事件(例如，心肌梗塞 心肌梗死、应激性心肌病和心脏性猝死)由于其不可预测性而令人担忧 以及缺乏关于致病机制的知识。心理社会应激源(如焦虑、个性 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 卒中。在心理社会压力的背景下，心脑相互作用的特征是一个重要的第一 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 已经提出，情绪和心理社会压力可能导致交感-儿茶酚胺能激增 降低心肌细胞活性和/或心脏功能。下丘脑精氨酸加压素与V1a 受体(V1aR)作为血管紧张素转换酶(AVP)对心理社会应激相关性心脏病具有巨大的治疗潜力 它的受体通过调节神经内分泌应激反应来促进健康和生存。主要论题 AVP通过V1aR发挥作用，通过动态调节促进健康和福祉 腹侧被盖区(VTA)对应激源的神经反应。AVP与应激相关疾病有关 人类和动物的情绪反应改变，这可以通过抗精神病药物治疗来调节， 提示在应激反应中存在AVP-VTA相互作用。然而，神经机制 AVP、AVPR1A基因表达、VTA依赖的应激反应和 心血管功能还没有得到充分的描述。为了解决这一知识差距，主要目标是 这项建议的目的是研究神经肽AVP的心脏保护特性和 确定AVPR1A基因表达、儿茶酚胺之间是否存在关联 在心理社会应激诱导的心肌损伤动物模型中，释放和心脏疾病结局。 许多易感个体暴露在多个风险因素中，这些因素经常相互作用，放大 心血管疾病风险。使用叙利亚仓鼠，我计划研究两只仓鼠之间的互动 心理社会风险因素、社会孤立和攻击性。目标1将检验VTA中AVP的假设 阻断应激诱导的儿茶酚胺释放和加重心肌缺血再灌注损伤，以及 目标2将检验V1aR基因表达模式将预测对压力和AVP反应的假设。 心脏损伤和儿茶酚胺的治疗。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知识；通过接受 来自经验丰富的研究人员的指导；并建立成功的独立研究计划。

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.