Central Nervous System Reprogramming of the Control of Blood Pressure Induced by Early Life Stress

早期生活压力引起的血压控制的中枢神经系统重新编程

• 批准号: 10555126
• 负责人: ALAN Kim JOHNSON
• 金额: $ 38.91万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555126
• 关键词: Acute; Address; Adult; Affect; Animals; Anti-Inflammatory Agents; Behavioral; Blood Pressure; Blood Vessels; Brain; Butyrates; Cardiovascular system; Cell Nucleus; Central Nervous System; Cerebrovascular system; Clinical; Collaborations; Consumption; Diet; Dietary Factors; Dietary Fats; Dietary Intervention; Disease; Eating; Epidemiology; Epigenetic Process; Etiology; Exercise; Exposure to; Fatty acid glycerol esters; Female; Foundations; Genetic; Glean; Hypertension; Immune system; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Investigation; Knowledge; Laboratories; Life; Macrophage; Macrophage Activation; Mediating; Mediator; Mental disorders; Methods; Modeling; Molecular; Mothers; Mus; Nervous System; Neural Pathways; Neuroanatomy; Neuronal Plasticity; Oxidative Stress; Pathogenesis; Pathology; Pharmaceutical Preparations; Physiological; Play; Process; Psychological Stress; Rattus; Renin-Angiotensin-Aldosterone System; Risk; Risk Factors; Rodent; Rodent Control; Role; Sex Differences; Site; Stimulus; Sympathetic Nervous System; Testing; Vascular Diseases; Weaning; Work; adverse childhood events; blood pressure control; blood pressure elevation; blood pressure regulation; brain pathway; cardiometabolism; cardiovascular disorder risk; cardiovascular risk factor; comparison control; cytokine; design; dietary; dietary salt; early life stress; experimental study; high salt diet; hypertensive; innovation; insight; male; maternal separation; neural network; neuroinflammation; novel; pharmacologic; postnatal; pre-clinical; prevent; programs; psychologic; psychological stressor; pup; resilience; response; sexual dimorphism; stressor; synergism; translational pipeline

PROJECT 2 SUMMARY Early life stress (ELS) acts as a strong etiological factor establishing conditions for subsequent stressors to trigger many psychological and physiological disorders. There is a strong association between adverse childhood experiences and cardiometabolic pathologies, including hypertension. When studying the role of the central nervous system (CNS) in the long-term regulation of blood pressure (BP), we discovered that the hypertensive response can be sensitized by exposure to mild stressors present earlier in life. Both Dr. Pollock’s laboratory (Project 1) and our laboratory (Project 2) have found that the psychological stress produced by repeated brief periods of maternal separation of rodent pups from their mothers (MaSep) will produce hypertensive response sensitization (HTRS). Our studies suggest that CNS inflammatory mechanisms play a key role in inducing and maintaining HTRS and therefore increased risk for cardiovascular disease. The central hypothesis of Project 2 is that the psychological stress of MaSep produces inflammatory mediators that reprogram the central neural network controlling sympathetic tone and BP and thereby exacerbates hypertension when new stressors are encountered in adulthood. Unfortunately, there are critical gaps in our understanding of exactly how ELS acts to induce the reprogramming of the CNS and maintain HTRS especially when it is expressed by ecologically relevant stressors such as eating high fat and high salt diets. Furthermore, we do not know what specific interventions can reverse the effects of ELS. The Specific Aims of Project 2 are designed to address these issues. Specific Aim 1 studies will determine whether the dietary risk factors of high dietary fat or salt (i.e., “second hits”) consumed after weaning exacerbate the hypertensive response in adult MaSep animals. Also, key brain nuclei controlling sympathetic tone and BP will be analyzed to identify molecular changes mediating HTRS. Specific Aim 2 will test the role of CNS inflammatory mechanisms in MaSep induction of HTRS and investigate strategies to reverse the effects of MaSep ELS and produce resilience. Project 2 is conceptually and technically innovative in that it tests an original hypothesis of how ELS sensitizes the hypertensive response to elicit frank HT in adults by using an experimental paradigm developed by the Johnson laboratory to separate the effects of HTRS induction from HTRS expression. Project 2 findings will provide important new information that will be relevant for directing the interpretation of results from other projects. Projects 1 and 2 enhance one another by both investigating the role of brain macrophages and inflammation in ELS-specific vascular dysfunction and HTRS. Project 2 will provide key mechanistic insights to both clinical projects (3 and 4) by clarifying involvement of dietary metabolites, exercise, and inflammation. New knowledge gained about mechanisms involved in HTRS will contribute to understanding the etiology and pathogenesis of essential HT and will provide valuable insights into intervention strategies for preventing high blood pressure.

项目2摘要 早期的生命压力（EL）是一个强大的病因学因素，为随后的压力源建立条件 引发许多心理和身体疾病。童年不利之间有很强的联系 经验和心脏代谢病理，包括高血压。在研究中央的角色时 在长期调节血压（BP）中，神经系统（CNS），我们发现高血压 反应可以通过暴露于生命早期的轻度压力源来敏感。波洛克博士的实验室 （项目1）和我们的实验室（项目2）发现，重复简短产生的心理压力 啮齿动物与母亲（MASEP）的孕产妇分离时期将产生高血压反应 灵敏度（HTRS）。我们的研究表明，CNS炎症机制在诱导和 维持HTR，因此增加了心血管疾病的风险。项目的中心假设 2是MASEP的心理压力产生炎症介质，以重新编程中央中性 网络控制同情语调和BP，从而加剧了新的压力源时的高血压 成年时遇到。不幸的是，我们对ELS的确切理解有关键的差距 诱导中枢神经系统的重编程并维护HTR，尤其是在生态上表达的时候 相关的压力源，例如吃高脂肪和高盐饮食。此外，我们不知道什么具体 干预措施可以扭转EL的影响。项目2的具体目标旨在解决这些问题 问题。具体目标1研究将确定高饮食脂肪或盐的饮食危险因素（即 断奶加剧了成年MASEP动物的高血压反应后，“第二次命中”。还， 将分析控制交感神经和BP的关键脑核，以鉴定介导的分子变化 HTRS。具体目标2将测试中枢神经系统炎症机制在HTRS的MASEP诱导中的作用 调查扭转MASEP EL的影响并产生弹性的策略。项目2在概念上是 从技术上讲，它检验了ELS如何感觉到高血压反应的原始假设 通过使用约翰逊实验室开发的实验范式来使成人弗兰克·HT（Frank HT）分开 HTRS表达诱导HTR的影响。项目2调查结果将提供重要的新信息 将与指导其他项目的结果解释有关。项目1和2增强一个 另一种是研究脑巨噬细胞的作用和注射在ELS特异性血管中的作用 功能障碍和HTRS。项目2将为两个临床项目（3和4）提供关键的机械见解 澄清饮食代谢产物，运动和炎症的参与。获得的新知识获得了 HTRS涉及的机制将有助于理解必需HT的病因和发病机理 并将为防止高血压的干预策略提供宝贵的见解。