MOLECULAR NEUROBIOLOGY OF DEPRESSION

这是通过以患者为中心的研究中的职业生涯中期调查员奖(K24)申请五年的工资支持。在我的整个职业生涯中，我一直试图在基本的神经生物学和临床领域之间架起一座桥梁，特别强调情绪障碍。到20世纪90年代初的S，我开始把精力转向一系列研究的发展，使用更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。通过使用成纤维细胞培养模型，我和我的合作者发现，抑郁症患者与与β肾上腺素受体相关的蛋白激酶A(PKA)调节亚单位的环状AMP结合减少。这会导致磷酸化活性(包括CREB)的降低和基因表达的改变。我们还利用差异显示逆转录聚合酶链式反应方法显示了一个特定的核磷酸酶基因的表达发生了变化。在这里，我概述了这些发现以及未来五年相关项目的计划。我还简要描述了介于基础研究和临床研究之间的另外两个项目领域。一个是使用新的临床评分工具(部分由我们的研究小组开发)来调查情绪调节，以测量药物操纵条件下的情绪成分。第二项代表了对难治性重度抑郁症的一种新的治疗干预。根据一组基本的实验室观察，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。总而言之，这些研究领域证明了我有能力一方面从基本的实验室发现过渡到临床现象学和治疗。最后，与K24的目标一致，我有来自多个学科的新调查人员的长期指导记录。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。这一奖项将使我摆脱许多这些要求，并将使我能够：1.发展基础分子生物学方法方面的进一步专业知识；2.开发面向未来资金机会的新项目；3.继续指导下一代研究人员。

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.