NORADRENERGIC SYSTEM IN DEPRESSION BIOLOGY

超出所提供的空间。此应用程序是为了支持Gregory A. Ordway博士作为一名独立的精神病学科学家的职业发展。alth研究。该候选人有15年的精神卫生研究历史，并在此期间获得了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衰退病理中的作用，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，目的是揭示药物或基因干预的新目标。拟议的职业发展包括加强和扩大派的知识基础的教育活动、提高和改进派的技术技能的小型休假以及加强合作的活动。上述各项建议的职业发展活动，旨在促进和加强私家侦探的研究生涯。拟议的研究将在一定程度上验证一种假设，即在重度抑郁症患者的去肾上腺素能系统（特别是蓝斑区）中存在明显的神经化学/神经解剖学缺陷。在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（以说明特异性）以及精神正常对照的受试者，将测量整个LC和主要边缘投影区（杏仁核）的特定蛋白质浓度。初步数据显示，无抗抑郁重度抑郁症患者LC中去甲肾上腺素转运蛋白（NET）水平低于对照组。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，人类体内的NET调节与去甲肾上腺素能稳态和抑郁症生物学有关。最近，P.I.表明，在暴露于某些NET抑制剂的情况下，NET明显下调。NET配体诱导的NET功能调控尚不清楚，但可能有助于其治疗作用机制。提出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）制备中诱导NET调节的能力，并研究这些作用的分子机制。重点将放在NET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减少的摄取超过体内抗抑郁药的存在。这一信息可能会显著影响NET抑制剂治疗抑郁症的治疗方案。总的来说，这些研究将揭示抑郁症中去甲肾上腺素能神经元的病理，新的药物治疗或遗传靶点的相关线索，以及NET配体抗抑郁药的分子机制。网站性能 ======================================== 节结束 ===========================================

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