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概要 早期生活压力（ELS）作为一个强大的病因因素，为随后的压力源建立条件， 引发许多心理和生理障碍。不良的童年生活 经验和心脏代谢疾病，包括高血压。在研究中央政府的作用时， 神经系统（CNS）在血压（BP）的长期调节中，我们发现高血压 早期生活中的轻微压力可以使这种反应敏感化。波洛克博士的实验室 （项目1）和我们的实验室（项目2）已经发现，重复简短的心理压力， 啮齿动物幼仔与其母亲的母体分离期（MaSep）将产生高血压反应 致敏（HTRS）。我们的研究表明，中枢神经系统炎症机制在诱导和 维持HTRS，因此增加心血管疾病的风险。项目的核心假设 2是MaSep的心理压力产生炎症介质， 控制交感神经张力和BP的神经网络，从而在新的应激源出现时加重高血压。 成年后遇到的。不幸的是，我们对ELS如何发挥作用的理解存在重大差距， 诱导CNS的重编程并维持HTRS，特别是当它在生态学上被表达时， 相关的压力源，如吃高脂肪和高盐饮食。此外，我们不知道具体是什么 干预措施可以逆转ELS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研究将确定高膳食脂肪或盐的饮食风险因素（即， “第二次打击”）使成年MaSep动物的高血压反应加剧。还有， 控制交感神经张力和血压的关键脑核将被分析，以确定介导 HTRS。具体目标2将测试CNS炎症机制在HTRS的MaSep诱导中的作用， 研究扭转MaSep ELS影响并产生弹性的策略。项目2在概念上和 技术上的创新之处在于它测试了ELS如何使高血压反应敏感化的原始假设， 通过使用由约翰逊实验室开发的实验范式， 从HTRS表达的HTRS诱导的作用。项目2的调查结果将提供重要的新信息， 将与指导其他项目结果的解释有关。项目1和2加强了一个 另一个是通过研究脑巨噬细胞和炎症在ELS特异性血管中的作用， 功能障碍和HTRS。项目2将通过以下方式为两个临床项目（3和4）提供关键的机制见解： 阐明饮食代谢物、运动和炎症的参与。获得的新知识 HTRS的发病机制将有助于理解原发性HT的病因和发病机制 并将为预防高血压的干预策略提供有价值的见解。