Lipid raft localization of Gs: a biomarker for depression and therapeutic response

Gs 的脂筏定位：抑郁症和治疗反应的生物标志物

• 批准号: 10620160
• 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: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620160
• 关键词: Adenylate Cyclase; Animal Model; Antidepressive Agents; Autopsy; Biochemical; Biological Markers; Biology; Blood Cells; Blood Platelets; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; Cell Fraction; Cell Line; Cells; Cementation; Chemicals; Chimeric Proteins; Chronic; Clinical; Coupling; Cultured Cells; Cyclic AMP; Data; Depressed mood; Depressive disorder; Disease remission; Dissociative Anesthetics; Event; Fright; Funding; GTP-Binding Protein alpha Subunits, Gs; Hallucinogens; Hamilton Rating Scale for Depression; Heterotrimeric GTP-Binding Proteins; Human; In Vitro; Individual; Ketamine; Knowledge; Link; Liquid substance; Measures; Membrane; Membrane Microdomains; Mental Depression; Military Personnel; Molecular; Molecular Profiling; Movement; Names; Neuroglia; Neurons; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Production; Property; Rapid screening; Research; Resistance; Role; Sampling; Screening procedure; Site; Speed; Suicide; System; Therapeutic; Time; Tissues; Translations; Tubulin; Veterans; Work; World Health Organization; antidepressant effect; biosignature; completed suicide; deacylation; disability; insight; military veteran; nerve stem cell; novel; novel diagnostics; novel therapeutics; palmitoylation; postsynaptic; presynaptic; response; service member; side effect; social stigma; suicidal risk; treatment duration; treatment response; uptake

Every day, 21 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, icreasing produciot of the intracelylar messenger, cAMP. 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 psychedelic or dissociative anesthetic 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 intent 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21名退伍军人完成自杀，主要是由于未经治疗的抑郁症的后果。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， 与腺苷酸环化酶结合，增加了细胞内的 信使cAMP抑郁自杀者的尸检组织显示恰恰相反， 脂质筏中包裹的Gsα的比例，初步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相关。 此外，几种迷幻或解离性麻醉剂化合物可能具有抗抑郁作用， 以及更短的治疗起效时间，拟议的研究将寻找细胞“生物特征”， 抗抑郁作用拟议的研究还将试图建立一个机械的理解， Gsα从脂筏的易位作为抑郁症的标志和作为抗抑郁作用的管道。 所提出的研究的一个目的是开发一个平台，该平台可以提供基于细胞的筛选，以确定是否存在假定的 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。另一 这些研究的目的是为抑郁症和早期（< 1周） 成功抗抑郁治疗的指标，可以发展成为临床上有用的，廉价的， 易于获得的生物标志物用于临床使用。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。

项目成果

Document of Trapani on animal consciousness and quantum brain function: A hypothesis.

特拉帕尼关于动物意识和量子大脑功能的文件：一个假设。

• DOI: 10.3233/jin-170070
• 发表时间: 2017
• 期刊: Journal of integrative neuroscience
• 影响因子: 1.8
• 作者: Cocchi,Massimo;Bernroider,G;Rasenick,Mark;Tonello,Lucio;Gabrielli,Fabio;Tuszynski,JackA
• 通讯作者: Tuszynski,JackA

Receptor signaling and the cell biology of synaptic transmission.

受体信号传导和突触传递的细胞生物学。

• DOI: 10.1016/b978-0-444-52002-9.00002-4
• 发表时间: 2012
• 期刊: Handbook of clinical neurology
• 作者: Yu,Jiang-Zhou;Rasenick,MarkM
• 通讯作者: Rasenick,MarkM