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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要重度抑郁症（MDD）是全球主要的健康问题，与抑郁症的发展直接相关心血管疾病（CVD）。尽管有许多因素可能有所贡献，但积累的证据人类和啮齿动物模型表明神经血管功能障碍在 MDD-CVD 中发挥致病作用合并症。一氧化氮 (NO) 生物利用度降低已成为抑郁症诱发的关键机制神经血管功能障碍；然而，分子介质尚不清楚。啮齿动物中令人信服的证据模型表明抑郁引起的一氧化氮生物利用度降低，继发于氧化应激的增加，介导周围血管和中枢神经功能障碍。然而，很少有研究直接检验患有MDD的健康成年人中NO介导的神经血管功能障碍的机制。有趣的是，绝经前女性的 CVD 风险低于男性，但罹患 CVD 的可能性却是男性的两倍多来自MDD。尽管这些数据强烈表明 MDD-CVD 病理生理学存在性别差异合并症，没有调查检查其机制基础中潜在的性别差异 MDD 中的神经血管失调。使用创新的转化人类方法，结合分子和生化技术，内皮功能的综合评估（微和大血管反应性）和交感神经系统活动的直接记录，这是该研究的目标拟议的研究是严格检查其他神经血管功能障碍的机制患有 MDD 的健康成年人。因此，我们的总体假设是氧化应激引起的失调 NO，无论是外周还是中枢，都是 MDD 神经血管功能障碍的基础，代表了一种机制抑郁症状与心血管疾病风险之间的联系。在具体目标 1 中，我们将研究外周 NO 在介导血管功能障碍中的机制作用患有重度抑郁症的男性和女性，重点关注氧化应激的作用。在具体目标 2 中，我们将研究中枢 NO 对患有重度抑郁症 (MDD) 的成人的交感神经抑制作用，还特别关注氧化应激的作用导致交感功能异常。最后，在具体目标 3 中，我们将研究以下因素的影响：慢性选择性5-羟色胺再摄取抑制剂治疗MDD对外周和中枢NO功能的影响。在每个目标中，我们将研究 MDD 引起的神经血管功能障碍的性别差异。研究结果有显着增进我们对神经血管功能障碍机制的理解的潜力 MDD 可能提供新的治疗靶点来减轻抑郁成人的 CVD 风险。这些项目将通过让申请人学习额外的知识，扩展申请人在综合神经心血管生理学方面的培训技术，包括人体血管组织的体外生化分析以及评估和通过诊断性精神病学访谈评估MDD。总之，这些研究有潜力建立和推进临床相关研究的新领域，同时提供强大的指导培训并指导专业发展，为 PI 过渡到独立而量身定制。在此外，已经确定了潜在的后续研究，这将是申请人职业生涯的关键要素进步并将促进她成为一名独立调查员的长期职业目标。