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: 10470346
• 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/10470346
• 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; Event; Exposure to; Fiber; Gene Expression; Gene Expression Profile; Genes; Goals; Grant; Health; Health Promotion; Heart; Heart Diseases; Heart Injuries; Heart failure; Housing; Human; Hypothalamic structure; Individual; Infarction; Injury; Knowledge; Lead; Link; Mentorship; Mesocricetus auratus; Microinjections; Midbrain structure; Modeling; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Neurons; Neuropeptides; Neurosecretory Systems; Odds Ratio; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Personal Satisfaction; Personality Traits; Physiological; Play; 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; 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; genetic epidemiology; heart function; implantation; improved; improved outcome; learning strategy; myocardial injury; neuromechanism; novel; predicting response; programs; protective effect; psychological distress; psychosocial; psychosocial stressors; receptor; relating to nervous system; 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.

项目摘要/摘要 心脏病是美国的主要死亡原因，并与脑血管一起 疾病占美国总死亡人数的28％以上。急性心脏事件（例如，心肌 梗塞，压力心肌病和心脏突然死亡）是因为它们的不可预测性 以及缺乏有关因果机制的知识。社会心理压力源（例如，焦虑，个性 特征，社会隔离）心血管系统负担过重，是心血管事件的风险因素和 中风。在社会心理压力的背景下，心灵互动的表征是重要的第一 识别与疾病风险增加有关的基因环境相互作用。研究人员 已经提出，情绪和社会心理压力可能会导致交感神经激素能激增， 降低心肌活性和/或心脏功能。下丘脑精氨酸 - 维息蛋白（AVP）和V1A 受体（V1AR）具有与AVP相关心脏病相关心脏病的巨大治疗潜力 及其受体通过调节神经内分泌压力反应来促进健康和生存。主要论文 该建议的是，通过V1AR行动，AVP通过动态调节来促进健康和福祉 腹侧对盖区域（VTA）对压力源的神经反应。 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来调节 在应力相关反应中提出AVP-VTA相互作用。但是，神经机制 是AVP，AVPR1A基因表达，VTA依赖性压力反应和 心血管功能尚未完全表征。为了解决这一知识的差距，主要目标 该建议的是研究神经肽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 释放和心脏病结局在心理压力引起的心肌损伤动物模型中。 许多易感人群暴露于经常相互作用的多种风险因素，放大 心血管疾病风险。使用叙利亚仓鼠，我计划研究两个 社会心理风险因素，社会隔离和侵略。 AIM 1将检验VTA中AVP的假设 阻止压力引起的儿茶酚胺释放和加剧心肌缺血 - 再灌注损伤，并 AIM 2将检验以下假设：V1AR基因表达模式将预测应力和AVP的反应 对心脏损伤和儿茶酚胺的治疗。学员还将参加职业发展活动： 了解如何进行心肌缺血 - 再灌注损伤手术并进行基因表达研究； 参加正式的职业发展计划；参加心血管遗传学的特殊计划 和流行病学；完整的科学课程以获得新知识；通过接受提高赠款写作技巧 经验丰富的研究人员的指导；并建立成功的独立研究计划。