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

精氨酸加压素和 V1A 受体在心理应激诱发的心肌损伤中的作用

• 批准号: 10671052
• 负责人: Mario Gil
• 金额: $ 9.91万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671052
• 关键词: Acute; Acute myocardial infarction; Address; Aggressive behavior; Animal Model; Animals; Antipsychotic Agents; Anxiety; Area; Argipressin; Biological; Blood; Brain; Cannulas; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Cause of Death; Cerebrovascular Disorders; Cessation of life; Collection; Communities; Coronary Arteriosclerosis; Coronary heart disease; Data; Disease Outcome; Emotional; Emotional Stress; Endocrine; Epidemiology; Event; Exposure to; Fiber; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Grant; Health; Health Promotion; Heart; Heart Diseases; Heart Injuries; Heart failure; Housing; Human; Hypothalamic structure; Individual; Infarction; Injury; Knowledge; Learning; Link; Mentorship; Mesocricetus auratus; Microinjections; Midbrain structure; Modeling; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Neurons; Neuropeptides; Neurosecretory Systems; Odds Ratio; Outcome; Pathway interactions; Patients; Personal Satisfaction; Personality Traits; Physiological; Play; Predisposition; Program Development; Property; Psychosocial Stress; Public Health; Receptor Gene; Reperfusion Injury; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Saline; Sex Differences; Signal Transduction; Social isolation; Stress; Stress cardiomyopathy; Stroke; Surgical Injuries; Sympathetic Nervous System; Syndrome; Testing; Therapeutic; Translating; United States; V1a vasopressin receptor; Ventral Tegmental Area; Ventricular; Work; Writing; acute stress; alternative treatment; behavioral response; biological adaptation to stress; brain tissue; cardioprotection; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; career development; disorder risk; emotional distress; experience; gene environment interaction; heart function; implantation; improved; improved outcome; myocardial injury; neural; neuromechanism; novel; predicting response; programs; psychological distress; psychosocial; psychosocial stressors; receptor; response; skills; stress management; stress related disorder; stressor; sudden cardiac death

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.

项目概要/摘要 心脏病与脑血管疾病一起是美国的首要死亡原因 在美国，疾病造成的死亡人数占总死亡人数的 28% 以上。急性心脏事件（例如心肌梗死） 梗塞、应激性心肌病和心源性猝死）因其不可预测性而令人担忧 以及缺乏对致病机制的了解。社会心理压力源（例如焦虑、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 中风。心理社会压力背景下心脑相互作用的表征是重要的首要任务 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 提出情绪和社会心理压力可能导致交感神经儿茶酚胺能激增 降低心肌细胞活力和/或心脏功能。下丘脑精氨酸加压素 (AVP) 和 V1A 受体（V1AR）对于心理社会压力相关的心脏病具有巨大的治疗潜力，如 AVP 及其受体通过调节神经内分泌应激反应来促进健康和生存。主要论文 该提案的主要内容是，AVP 通过 V1AR 发挥作用，通过动态调节来促进健康和福祉 腹侧被盖区（VTA）对应激源的神经反应。 AVP 与压力相关疾病有关 人类和动物的情绪反应改变，可以通过抗精神病治疗来调节， 表明 AVP-VTA 在压力相关反应中相互作用。然而，神经机制 AVP、Avpr1a 基因表达、VTA 依赖性应激反应和 心血管功能尚未完全表征。为了解决这一知识差距，主要目标 该提案的目的是研究神经肽 AVP 的心脏保护特性和 确定 Avpr1a 基因表达与儿茶酚胺之间是否存在关联 心理社会应激引起的心肌损伤动物模型中的释放和心脏病结果。 许多易感人群面临多种风险因素，这些因素经常相互作用，放大风险 心血管疾病风险。我计划使用叙利亚仓鼠来研究两只仓鼠之间的相互作用 社会心理危险因素、社会孤立和攻击性。目标 1 将检验 VTA 中 AVP 的假设 阻止应激诱导的儿茶酚胺释放和心肌缺血再灌注损伤的加剧，以及 目标 2 将检验 V1AR 基因表达模式将预测对压力和 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；参加心血管遗传学特别计划 和流行病学；完成科学课程以获得新知识；通过接收提高拨款写作技巧 来自经验丰富的调查人员的指导；并建立成功的独立研究计划。