MOLECULAR NEUROBIOLOGY OF DEPRESSION

抑郁症的分子神经生物学

• 批准号: 6391435
• 负责人: Richard Charles Shelton
• 金额: $ 10.63万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6391435
• 关键词: antipsychotic agents; beta adrenergic receptor; biopsy; bupropion; cAMP response element binding protein; clinical research; combination chemotherapy; drug resistance; electromyography; enzyme activity; fibroblasts; fluoxetine; gene expression; human subject; luciferin monooxygenase; major depression; mental disorder chemotherapy; neuropharmacology; neurophysiology; plasmids; polymerase chain reaction; protein kinase A; receptor sensitivity; startle reaction; tissue /cell culture

This is a request for five years of salary support via the Midcareer Investigator Award in Patient-Oriented Research (K24). Throughout my career I have sought to bridge basic neurobiological and clinical domains, with special emphasis on mood disorders. By the early 1990's, I began to redirect my energies toward the development of a series of studies using newer molecular biological methods to investigate the causes and possible treatments for depression. Using a fibroblast cell culture model, my collaborators and I have discovered that melancholic major depressives have a reduction of cyclic AMP binding to the regulatory subunit of protein kinase A (PKA) linked to beta adrenoceptors. This results in a concomitant reduction in phosphorylation activity (including that of CREB) and altered gene expression. We also have shown an altered expression of a specific nuclear phosphatase gene using the differential display reverse transcription polymerase chain reaction methodology with cPCR. Herein, I have outlined these findings along with plans for related projects over the next five years. I also have described briefly two other project areas that stand in the mid-ground between basic and clinical investigations. One is an investigation of mood regulation using new clinical ratings instruments (developed, in part by our research group) to measure components of mood under conditions of pharmacological manipulation. The second represents a novel therapeutic intervention in refractory major depression. Drawing from a set of basic laboratory observations, I have conducted a successful trial of the combination of olanzapine and fluoxetine in refractory depressives. Together, these study areas demonstrate my capacity to bridge from basic laboratory findings, on the one hand, to clinical phenomenology and treatment, on the other. Finally, consistent with the goals of the K24, I have a long track-record of mentorship of new investigators from a number of disciplines. However, an increasing burden of administrative and clinical responsibilities threatens my research productivity and mentorship. This award will relieve me of many of these demands and will allow me to: 1.Develop further expertise in basic molecular biological methods; 2. Develop new projects oriented to future funding opportunities; and 3. Continue to mentor the next generation of investigators.

这是通过以患者为导向的研究人员奖（K24）获得五年薪水支持的要求。在我的整个职业生涯中，我一直试图桥接基本的神经生物学和临床领域，并特别强调情绪障碍。 到1990年代初期，我开始将能量重定向到一系列研究的发展，使用较新的分子生物学方法研究抑郁症的原因和可能的治疗方法。 我和我的合作者使用成纤维细胞培养模型，发现忧郁的主要抑郁剂减少了与βadrenoceptors相关的蛋白激酶A（PKA）调节亚基的环状AMP结合。 这会导致磷酸化活性（包括CREB的磷酸化活性）和基因表达改变。 我们还使用差分显示逆转录聚合酶链反应方法与CPCR显示了特定核磷酸酶基因的表达改变。 在此，我在未来五年内概述了这些发现以及相关项目的计划。 我还简要描述了基本和临床调查之间地下的其他两个项目区域。 一种是使用新的临床评级工具（部分由我们的研究小组开发的）对情绪调节的研究，以测量药理学操纵条件下的情绪组成部分。 第二个代表了在难治性重大抑郁症中的新型治疗干预措施。 从一组基本的实验室观察中，我成功地进行了一项成功的试验，该试验是奥氮平和氟西汀在难治性抑郁症中的结合。 这些研究领域共同证明了我有能力从基本的实验室发现桥接到另一方面的临床现象学和治疗。 最后，与K24的目标一致，我从许多学科的新调查人员中拥有长期的指导。 但是，行政和临床责任的越来越负担威胁着我的研究生产力和指导。 该奖项将使我减轻许多要求，并允许我：1。基本分子生物学方法的进一步专业知识； 2。开发针对未来资金机会的新项目；和3。继续指导下一代调查人员。