Peripheral and Central Mechanisms of Neurovascular Dysfunction in Human Depression

项目总结 严重抑郁障碍(MDD)是一个主要的全球健康问题，与 心血管疾病(CVD)。尽管许多因素可能起到了作用，但从 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)生物利用度降低已成为抑郁症的一个关键机制 神经血管功能障碍；然而，分子介质尚不清楚。关于啮齿动物的令人信服的证据 模型表明，抑郁导致NO生物利用度降低，继而是氧化应激增加， 调节外周血管和中枢神经功能障碍。然而，很少有研究直接考察 一氧化氮介导的神经血管功能障碍在患有MDD的健康成人中的潜在机制。 有趣的是，绝经前女性患心血管疾病的风险比男性低，但罹患心血管疾病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的病理生理学上存在性别差异 合并症，还没有研究检查潜在的性别差异的机制基础 MDD患者的神经血管调节失调。使用创新的翻译人工方法，将 分子和生化技术，内皮功能的综合评估(显微和 大血管反应性)和直接记录交感神经系统活动，目标是 建议的研究是严格检查(S)在其他方面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，氧化剂应激诱导的细胞功能失调 不，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 抑郁症状和心血管疾病风险之间的联系。 在特定的目标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。 男性和女性患有MDD，强调氧化应激的作用。在具体目标2中，我们将研究 中枢NO在成人MDD中的交感神经抑制作用，也特别关注氧化应激的作用 导致异常的交感神经功能。最后，在具体目标3中，我们将调查 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，我们将调查MDD引起的神经血管功能障碍的性别差异。研究结果表明 显著提高我们对神经血管功能障碍机制的理解的潜力 并可能提供新的治疗靶点，以降低成年抑郁症患者患心血管疾病的风险。这些项目将 延长申请者的神经-心血管综合生理学培训，允许她学习其他 技术，包括人体血管组织的体外生化分析和评估和 通过精神病学诊断访谈对MDD进行评估。总而言之，这些研究有可能 建立和推进临床相关研究的新领域，同时提供强有力的 指导培训和指导专业发展，为PI向独立过渡量身定做。在……里面 此外，已经确定了潜在的后续研究，这将是申请人职业生涯中的关键要素 并将促进她成为一名独立调查员的长期职业目标。

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.