NORADRENERGIC SYSTEM IN DEPRESSION BIOLOGY

超出提供的空间。这项申请是为了支持格雷戈里·A·奥德韦博士作为心理健康研究领域的独立科学家的职业发展。该候选人在心理健康研究方面有15年的历史，并在S时期得到了国立卫生研究院的资助。他的主要研究领域集中在中枢去甲肾上腺素系统在退行性病变中的作用，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，目的是揭示药物或遗传干预的新靶点。拟议的职业发展包括加强和扩大私人助理的知识基础的教育活动、促进和改进私人助理的技术技能的迷你休假以及加强合作的活动。综上所述，拟议的职业提升活动旨在促进和加强私人投资公司的研究事业。这项拟议的研究将在一定程度上检验一种假设，即在重度抑郁症的去甲肾上腺素系统(特别是蓝斑；LC)中存在明显的神经化学/神经解剖学缺陷。在整个LC过程中，将测量死亡时患有严重抑郁症的受试者、患有其他精神疾病的受试者以及精神正常的对照组受试者的死后大脑中主要边缘投射区域(杏仁核)的特定蛋白质浓度。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LC中去甲肾上腺素转运体(NET)水平较低。这些和其他数据表明，抑郁症与去甲肾上腺素缺乏有关，并进一步表明，人类的净调节与去甲肾上腺素能动态平衡和抑郁症生物学有关。最近，P.I.显示，暴露于某些Net抑制剂后，Net的表达显著下调。对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。这项研究的第二个组成部分是阐明配体诱导的网络调节的分子机制。将研究Net配体在体外(细胞培养)和体内(大鼠)准备中诱导Net调节的能力，并探讨导致这些影响的分子机制。重点将放在净调节和恢复的时间方面，因为从抑制剂诱导的下调中缓慢恢复可能意味着体内摄取减少超过抗抑郁药的存在。这一信息可能对治疗抑郁症的Net抑制剂的治疗方案产生重大影响。总体而言，拟议的研究将揭示抑郁症去甲肾上腺素能神经元的病理，与新的药物治疗或遗传靶点相关的线索，以及净配体抗抑郁剂的分子机制。表演网站========================================Section End===========================================

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===========================================