MOLECULAR NEUROBIOLOGY OF DEPRESSION

这是一份通过面向患者的研究（K24）的职业中期研究者奖获得五年薪水支持的申请。在我的职业生涯中，我一直在寻求基础神经生物学和临床领域的桥梁，特别强调情绪障碍。到20世纪90年代初，我开始将精力转移到一系列研究的发展上，这些研究使用较新的分子生物学方法来调查抑郁症的原因和可能的治疗方法。利用成纤维细胞培养模型，我和我的合作者发现，忧郁型重度抑郁症患者与β肾上腺素受体相关的蛋白激酶a （PKA）调节亚基的环AMP结合减少。这导致伴随的磷酸化活性降低（包括CREB）和基因表达改变。我们也显示了一个特定的核磷酸酶基因的表达改变使用差异显示逆转录聚合酶链反应方法与cPCR。在此，我概述了这些发现以及未来五年相关项目的计划。我还简要地描述了另外两个介于基础研究和临床研究之间的项目领域。一个是使用新的临床评级工具（部分由我们的研究小组开发）来测量药物操纵条件下的情绪成分，对情绪调节进行调查。第二个代表了一种新的治疗干预难治性重度抑郁症。根据一系列基本的实验室观察，我成功地进行了奥氮平和氟西汀联合治疗难治性抑郁症的试验。总之，这些研究领域展示了我从基础实验室发现到临床现象学和治疗的桥梁能力。最后，与K24的目标一致的是，我长期以来一直在指导来自多个学科的新研究者。然而，越来越多的行政和临床责任的负担威胁到我的研究效率和指导。这个奖项将使我从这些要求中解脱出来，使我能够：进一步发展基本分子生物学方法方面的专业知识；2. 开发面向未来融资机会的新项目；和3。继续指导下一代调查员。

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.