BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10515297
• 负责人: MARK M. RASENICK
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515297
• 关键词: Adenylate Cyclase; Advocacy; American; Animal Model; Antidepressive Agents; Area; Autopsy; Award; Biological Markers; Biology; Biomedical Research; Blood Cells; Blood Tests; Brain; Cell Fraction; Cells; Chemicals; Chimeric Proteins; Chronic; Clinical; Clinical Research; Cultured Cells; Cyclic AMP; Cytoskeleton; Data; Depressed mood; Depressive disorder; Disease; Disease remission; Economics; Elements; Event; Fish Oils; Foundations; Fright; Funding; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Health; Heterotrimeric GTP-Binding Proteins; Human; In Vitro; Individual; Investigation; Justice; Ketamine; Knowledge; Laboratories; Link; Lipids; Marketing; Measures; Membrane Microdomains; Mental Depression; Mental disorders; Methodology; Military Personnel; Molecular; Molecular Profiling; Mood Disorders; Movement; Myocardial Ischemia; Neuroglia; Neurons; Omega-3 Fatty Acids; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Positioning Attribute; Production; Property; Public Policy; Rapid screening; Research; Resistance; Science; Scientist; Screening procedure; Shapes; Signaling Protein; Site; Social Justice; Social Work; Speed; Suicide; Synapses; System; Therapeutic; Time; Tissues; Translating; Triton X100; Tubulin; Veterans; Wood material; Work; World Health Organization; antidepressant effect; biosignature; career; completed suicide; design; disability; experience; insight; military veteran; novel; peace; postsynaptic; presynaptic; response; sabbatical; side effect; social stigma; suicidal risk; treatment duration; treatment response; uptake

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.

每天都有22名退伍军人自杀，主要是由于未经治疗的抑郁症。由于 恐惧和耻辱，许多人不寻求治疗。对于那些这样做的人，大约三分之一的时间，没有药物提供 缓解，甚至那些抗抑郁药，做工作往往需要6-8周前治疗起效。 不幸的是，目前还没有关于抗抑郁药（或抗抑郁药）作用的分子/细胞基础的统一假设。 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， 行动上为此，我们已经观察到培养的神经或神经胶质细胞的慢性处理（3-5天）， 与许多化学上不同的抗抑郁化合物一起， 从脂筏中分离出来，并与腺苷酸环化酶紧密结合。尸体上的组织 而自杀者则相反，脂质筏中包裹的Gsα比例增加， 数据表明，这也在血细胞中观察到，其中脂筏中Gsα的程度与 抑郁症和抗抑郁药的临床反应。此外，几种实验化合物可 具有抗抑郁作用，治疗起效时间较短，拟议的研究将寻找一种 抗抑郁作用的细胞“生物特征”。拟议的研究还将试图建立一个机制， 了解Gsα从脂筏的易位作为抑郁症的标志和作为一个管道， 抗抑郁作用其中一个方面涉及抗抑郁药之间的相互作用的调查 和脂质，特别是鱼油中的ω 3多不饱和脂肪酸（DHA和EPA）。另一个目的 涉及微管蛋白在脂筏中形成Gsα的锚的可能性。的一个潜在应用 拟议的研究是开发一个平台，可以提供一个基于细胞的筛选推定的抗抑郁药 化合物以及筛选工具，以指示个性化的抗抑郁药选择。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，可以发展成为一个临床上有用的，廉价的，容易- 可用于临床的生物标志物。抗抑郁作用途径的确定可能导致 新的抗抑郁药物，而抑郁症的定量值的分配可能有助于克服 耻辱和鼓励成千上万的抑郁症退伍军人寻求治疗。