Peripheral and Central Mechanisms of Neurovascular Dysfunction in Human Depression

人类抑郁症神经血管功能障碍的外周和中枢机制

• 批准号: 9306246
• 负责人: Jody Greaney
• 金额: $ 10.47万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306246
• 关键词: Adult; Antidepressive Agents; Antioxidants; Area; Attenuated; Biochemical; Biological Availability; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular Physiology; Chronic; Clinical Data; Comorbidity; Data; Depressed mood; Development; Diagnostic; Disease remission; Elements; Evaluation; Female; Follow-Up Studies; Fostering; Functional disorder; Goals; Human; Impairment; In Vitro; Interview; Investigation; Learning; Link; Major Depressive Disorder; Mediating; Mediator of activation protein; Mental Depression; Mentors; Molecular; Nerve; Neuraxis; Neuronal Dysfunction; Neurophysiology - biologic function; Nitric Oxide; Nitric Oxide Synthase; Outcome; Pathogenicity; Peripheral; Pharmacotherapy; Play; Premenopause; Production; Reactive Oxygen Species; Research; Research Personnel; Rodent; Rodent Model; Role; Secondary to; Selective Serotonin Reuptake Inhibitor; Sex Characteristics; Sympathetic Nervous System; System; Techniques; Tissues; Training; Vascular Diseases; Vasodilation; Woman; cardiovascular disorder risk; cardiovascular risk factor; career; clinically relevant; depression model; depressive symptoms; global health; improved; in vivo; indexing; innovation; insight; male; men; neurovascular; new therapeutic target; novel; oxidant stress; vascular endothelial dysfunction

PROJECT SUMMARY Major depressive disorder (MDD) is a major global health concern and is directly linked to the development of cardiovascular disease (CVD). Although a number of factors may contribute, accumulating evidence from humans and rodent models indicates that neurovascular dysfunction plays a pathogenic role in MDD-CVD comorbidity. Reduced nitric oxide (NO) bioavailability has emerged as a key mechanism in depression-induced neurovascular dysfunction; however, the molecular mediators are unclear. Compelling evidence in rodent models suggests depression-induced reductions in NO bioavailability, secondary to increases in oxidant stress, mediate peripheral vascular and central neural dysfunction. However, few studies have directly examined the mechanisms underlying NO-mediated neurovascular dysfunction in otherwise healthy adults with MDD. Interestingly, premenopausal women have lower CVD risk than men, yet are more than twice as likely to suffer from MDD. Although these data strongly suggest sex differences in the pathophysiology of MDD-CVD comorbidity, no investigations have examined potential sex differences in the mechanistic underpinnings of neurovascular dysregulation in MDD. Using an innovative translational human approach that combines molecular and biochemical techniques, a comprehensive assessment of endothelial function (micro- and macro-vascular reactivity) and direct recordings of sympathetic nervous system activity, the goal of the proposed studies is to rigorously examine the mechanism(s) underlying neurovascular dysfunction in otherwise healthy adults with MDD. Accordingly, our overall hypothesis is that oxidant stress–induced dysregulation of NO, both peripherally and centrally, underlies neurovascular dysfunction in MDD, representing a mechanistic link between depressive symptoms and CVD risk. In Specific Aim 1, we will examine the mechanistic role of peripheral NO in mediating vascular dysfunction in men and women with MDD, with emphasis on the role of oxidant stress. In Specific Aim 2, we will examine the sympathoinhibitory role of central NO in adults with MDD, also with specific focus on the role of oxidant stress in contributing to aberrant sympathetic function. Finally, in Specific Aim 3, we will investigate the influence of chronic selective serotonin reuptake inhibitors for the treatment of MDD on peripheral and central NO function. In each aim, we will investigate sex differences in MDD-induced neurovascular dysfunction. The findings have the potential to significantly advance our understanding of the mechanisms of neurovascular dysfunction in MDD and may provide novel therapeutic targets to alleviate CVD risk in depressed adults. These projects will extend the applicant's training in integrative neuro-cardiovascular physiology by allowing her to learn additional techniques, including in vitro biochemical analyses of human vascular tissue and the assessment and evaluation of MDD via diagnostic psychiatric interviews. In summary, these studies have the potential to establish and advance a novel area of clinically relevant research, while simultaneously providing strong mentored training and guided professional development, tailored to transition the PI to independence. In addition, potential follow-up studies have been identified that will be critical elements in the applicant's career progression and will foster her long-term career goal of becoming an independent investigator.

项目摘要 重度抑郁症（MDD）是全球主要的健康问题，与发展直接相关 心血管疾病（CVD）。尽管许多因素可能导致，从而积累了证据 人类和啮齿动物模型表明，神经血管功能障碍在MDD-CVD中起致病作用 合并症。一氧化氮（NO）的生物利用度降低已成为抑郁症引起的关键机制 神经血管功能障碍；但是，分子介质尚不清楚。啮齿动物中有令人信服的证据 模型表明，抑郁症引起的无生物利用度减少，其次是氧化物应激的增加， 介导外周血管和中央神经功能障碍。但是，很少有研究直接研究 在其他健康成年人中，无介导的神经血管功能障碍的机制。 有趣的是，绝经前妇女的CVD风险低于男性，但遭受痛苦的可能性是 尽管这些数据强烈建议MDD-CVD病理生理学的性别差异 合并症，没有调查检查在机械基础上的潜在性别差异 MDD中的神经血管失调。使用创新的翻译人类方法 分子和生化技术，对内皮功能的全面评估 宏 - 血管反应性）和交感神经系统活动的直接记录，目的 拟议的研究是严格检查否则的神经血管功能障碍的机制 具有MDD的健康成年人。彼此之间，我们的总体假设是氧化应激诱导的失调 不，在外围和中央，MDD中神经血管功能障碍的基础，代表机械 抑郁症状与CVD风险之间的联系。 在特定的目标1中，我们将研究外围NO在介导血管功能障碍中的机械作用 具有MDD的男性和女性，重点是氧化物胁迫的作用。在特定目标2中，我们将研究 中央NO在MDD成年人中的交感抑制作用，还特别关注氧化物应激的作用 在促进异常的交感神经功能方面。最后，在特定目标3中，我们将研究 慢性选择性5-羟色胺再摄取抑制剂，用于治疗MDD在外周和中央NO功能上。 在每个目标中，我们将研究MDD诱导的神经血管功能障碍的性别差异。发现有 显着提高我们对神经血管功能障碍机制的理解的潜力 MDD并可能提供新颖的治疗靶标，以减轻成年人抑郁症的CVD风险。这些项目将 通过允许她学习其他 技术，包括人血管组织的体外生化分析以及评估和 通过诊断精神病访谈评估MDD。总而言之，这些研究有可能 建立并推进了临床相关研究的新型领域，同时提供了强大的研究 为了将PI转变为独立性，介绍了训练和指导专业发展。在 此外，已经确定了潜在的后续研究，这将是申请人职业的关键要素 进步，并将促进她成为独立调查员的长期职业目标。