NORADRENERGIC SYSTEM IN DEPRESSION BIOLOGY

超出所提供的空间。 本申请旨在支持Gregory A博士的职业发展。奥德韦是精神健康研究的独立科学家。候选人有15年的心理健康研究历史，并在此期间得到了NIMH的资助。他的主要研究领域集中在中枢去甲肾上腺素能系统在退行性疾病病理学中的作用，以及去甲肾上腺素能抗抑郁药物的分子机制。PI建议继续他的研究，以阐明抑郁症的基本神经化学病理学，旨在揭示药理学或遗传干预的新靶点。拟议的职业发展包括加强和扩大少年派知识基础的教育活动，提高和改善少年派技术技能的小型休假，以及加强合作的活动。建议的职业发展活动旨在促进和提高主要研究者的研究事业。拟议中的研究将部分地检验这一假设，即在重性抑郁症中去甲肾上腺素能系统（特别是蓝斑; LC）中发生了一系列不同的神经化学/神经解剖缺陷。将在整个LC中测量特定蛋白质的浓度，并在死亡时患有重度抑郁症的受试者、患有其他精神疾病的受试者（以解决特异性）和精神病学正常对照受试者的死后大脑的主要边缘投射区（杏仁核）中测量特定蛋白质的浓度。 初步数据显示，与对照组相比，无抗抑郁药的重度抑郁症受试者的LC中去甲肾上腺素转运蛋白（NET）水平较低。这些和其他数据暗示抑郁症与去甲肾上腺素缺乏有关，并进一步表明人类NET调节与去甲肾上腺素能稳态和抑郁症生物学有关。最近，PI表明NET在对某些NET抑制剂的抑制下被稳健地下调。NET配体诱导的NET功能的调节知之甚少，但可能有助于其治疗作用的机制。拟议的研究的第二个组成部分是阐明负责配体诱导的NET调节的分子机制。将研究NET配体在体外（细胞培养）和体内（大鼠）制剂中诱导NET调节的能力，并研究导致这些效应的分子机制。重点将放在NET的调节和恢复的时间方面，因为缓慢的恢复从走廊诱导的下调可能意味着减少摄取超过抗抑郁药在体内的存在。这些信息可能会显着影响NET抑制剂治疗抑郁症的治疗方案。总体而言，拟议的研究将揭示抑郁症中去甲肾上腺素能神经元的病理学，与新的药理学或遗传靶点相关的线索，以及NET配体抗抑郁药的分子机制。性能现场=

EXCEED THE SPACE PROVIDED. This application is to support the career development of Dr. Gregory A. Ordway as an independent scientist in mental he'.alth research. The candidate has a 15 year history in mental health research and has been funded by NIMH during th s time. His primary area of research has focused on the role of the central noradrenergic system in the pathology of degression, as well as on molecular mechanisms of noradrenergic antidepressant drugs. The PI proposes to continue his research to elucidate the basic neurochemical pathology of depression with the intention of revealing novel targets fo ¿ pharmacological or genetic intervention. The proposed career development includes educational activities to enhance and broaden the Pi's knowledge base, mini-sabbaticals to advance and improve the Pi's technical skills, and activities to strengthen collaborations. Together, the proposed career enhancement activities are designed to facilitate ard enhance the research career of the PI. The proposed research will, in part, test the hypothesis that a distinct constellation of neurochemical/neuroanatomical deficits occurs in the noradrenergic system (in particular, the locus coeruleus; LC) in major depression. Concentrations of specific proteins will be measured throughout the LC, and in a major limbic projection area (amygdala) in post-mortem brains from subjects with major depression at the time of death, subjects with other psychiatric illnesses (to address specificity), and from psychiatrically normal control subjects. Preliminary data reveals low levels of norepinephrine transporter (NET) in the LC of antidepressant-free major depressive subjects relative to control subjects. These and other data imply that depression is associated with a norepinephrine deficiency, and further suggest that NET regulation in humans is relevant to noradrenergic homeostasis and depression biology. Recently, the P.I. showed that the NET is robustly downregulated in response to exposureto certain NET inhibitors. The regulation of NET function induced by NET ligands is poorly understood but may contribute to their mechanism of therapeutic action. A second component of the proposed research is to elucidate the molecular mechanisms responsible for ligand-induced regulation of the NET. The ability of NET ligands to induce NET regulation in in vitro (cell culture) and in vivo (rat) preparations will be studied, and the molecular mechanisms responsible for those effects will be investigated. Emphasis will be placed on temporal aspects of NET regulation and recovery, because slow recovery from inhibitor-induced down-regulation may imply that reduced uptake exceeds antidepressant presence in vivo. This information could significantly impact treatment regimens of NET inhibitors for management of depression. Overall, the proposed studies will reveal pathology of noradrenergic neurons in depression, clues relevant to new pharmacotherapeutic or genetic targets, and molecular mechanisms of NET ligand antidepressants. PERFORMANCE SITE ========================================Section End===========================================