BLR&D Research Career Scientist Award Application

每天都有 22 名退伍军人自杀，主要原因是抑郁症未经治疗造成的后果。由于 由于恐惧和耻辱，许多人不寻求治疗。对于那些这样做的人来说，大约三分之一的时间，没有提供毒品 甚至那些确实有效的抗抑郁药也通常需要 6-8 周才能开始治疗。 不幸的是，对于抗抑郁药物（或 抑郁症）已经出现。在过去的几年里，我们建议，除了 突触前靶点（摄取位点），许多抗抑郁药物具有突触后机制 行动。为此，我们观察到对培养的神经细胞或神经胶质细胞进行长期治疗（3-5天） 与许多化学性质不同的抗抑郁化合物一起易位异三聚体 G 蛋白 Gsα 脱离脂筏并与腺苷酸环化酶建立更密切的联系。抑郁症患者的死后组织 自杀者的情况恰恰相反，脂筏中聚集的 Gsα 比例增加，并且初步 数据表明，这也在血细胞中观察到，脂筏中 Gsα 的程度与两者相关 抑郁症和抗抑郁药的临床反应。此外，一些实验化合物可能 具有抗抑郁作用以及较短的治疗起效，拟议的研究将寻找一种 抗抑郁作用的细胞“生物特征”。拟议的研究还将尝试建立一个机制 了解 Gsα 从脂筏的易位作为抑郁症的标志和作为抑郁症的渠道 抗抑郁作用。其中一方面涉及抗抑郁药之间相互作用的研究 和脂质，特别是鱼油中的 omega 3 多不饱和脂肪酸（DHA 和 EPA）。另一个目标 涉及微管蛋白在脂筏中形成 Gsα 锚的可能性。该方法的一个潜在应用是 拟议的研究是开发一个平台，可以为假定的抗抑郁药物提供基于细胞的筛选 化合物以及表明个性化抗抑郁药物选择的筛选工具。这些的另一个意图 研究的目的是提供抑郁症的外周组织生物标志物和抑郁症的早期（< 1 周）指标 成功的抗抑郁治疗方法可以开发成一种临床上有用的、廉价的且易于使用的方法 可供临床使用的生物标志物。抗抑郁作用途径的确定可能会导致 新型抗抑郁药物，而为抑郁症指定定量值可能有助于克服 耻辱并鼓励数千名抑郁的退伍军人寻求治疗。

Every day, 22 veterans complete suicide, primarily due to the ramifications of untreated depression. Due to fear and stigma, many do not seek treatment. For those who do, about one third of the time, no drug offers relief and even those antidepressants that do work often require 6-8 weeks before therapeutic onset. Unfortunately, no unifying hypothesis for a molecular/cellular basis of action for antidepressant drugs (or depressive disorders) has emerged. Over the last several years, we have suggested that, in addition to presynaptic targets (uptake sites), a number of antidepressant drugs have a post-synaptic mechanism of action. Toward this end, we have observed that chronic treatment (3-5 days) of cultured neural or glial cells with a number of chemically diverse antidepressant compounds translocates the heterotrimeric G protein Gsα out of lipid rafts and into a closer association with adenylyl cyclase. Post-mortem tissue from depressed suicides shows just the opposite, with an increased proportion of Gsα ensconsed in lipid rafts and preliminary data suggest that this is also observed in blood cells, where the extent of Gsα in lipid rafts correlates with both depression and clinical response to antidepressants. Furthermore, several experimental compounds may have antidepressant effects as well as shorter therapeutic onset, and the proposed studies will search for a cellular “biosignature” for antidepressant action. Proposed studies will also attempt to establish a mechanistic understanding for the translocation of Gsα from lipid rafts as a hallmark of depression and as a conduit for antidepressant action. One aspect of this involves an investigation of the interactions between antidepressants and lipids, particularly the omega 3 polyunsaturated fatty acids from fish oil (DHA and EPA). Another aim involved the possibility that tubulin forms the anchor for Gsα in lipid rafts. One potential application of the proposed studies is to develop a platform that can provide a cell-based screen for putative antidepressant compounds as well as a screening tool to indicate personalized antidepressant choice. Another intent of these studies is to provide a peripheral tissue biological marker for depression and an early (< 1 week) indicator of successful antidepressant treatment that can be developed into a clinically useful, inexpensive and readily- available biomarker for clinical use. The identification of a pathway for antidepressant action might lead to novel antidepressant drugs, while the assignation of a quantitative value for depression may help overcome stigma and encourage thousands of depressed veterans to seek treatment.