BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10047284
• 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/10047284
• 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; Data; Depressed mood; Depression and Suicide; Depressive disorder; Disease; 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; Lead; Link; Lipids; 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; base; biosignature; career; completed suicide; design; disability; experience; insight; military veteran; novel; peace; 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，主要原因是未经治疗的抑郁症的后果。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里，没有药物提供 缓解，甚至那些有效的抗抑郁药物，通常需要6-8周才能开始治疗。 不幸的是，没有关于抗抑郁药物分子/细胞作用基础的统一假设(或 抑郁障碍)已经出现。在过去的几年里，我们已经建议，除了 突触前靶点(摄取部位)，一些抗抑郁药物具有突触后机制 行动。为此，我们观察到慢性处理(3-5天)培养的神经或神经胶质细胞 与许多化学上不同的抗抑郁化合物一起易位的异源三聚体G蛋白Gsα 走出脂筏，进入与腺酰环化酶更紧密的结合。抑郁症的尸检组织 自杀的情况正好相反，Gsα存在于脂筏中的比例增加，初步 数据表明，这也可以在血细胞中观察到，其中脂筏中Gsα的程度与这两种情况相关 抑郁与抗抑郁药物的临床反应。此外，几种实验化合物可能 具有抗抑郁作用和较短的治疗起效时间，拟议的研究将寻找一种 抗抑郁作用的细胞“生物签名”。拟议的研究还将试图建立一种机械的 理解从脂筏中移位Gsα是抑郁症的标志和治疗抑郁症的途径 抗抑郁作用。其中一个方面是研究抗抑郁剂之间的相互作用。 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的锚定的可能性。该技术的一个潜在应用 建议的研究是开发一个平台，可以为可能的抗抑郁药物提供基于细胞的筛选 此外，该公司还提供了一种筛选工具，用于显示个性化的抗抑郁药选择。这些人的另一个意图 研究旨在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。 成功的抗抑郁药物治疗，可以开发成临床上有用的，廉价的，容易- 可供临床使用的生物标志物。识别抗抑郁作用的途径可能会导致 新的抗抑郁药物，而为抑郁症指定一个量化的值可能有助于克服 羞辱和鼓励数千名抑郁的退伍军人寻求治疗。