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更紧密地结合，增加细胞内细胞的产生 信使，营。抑郁症自杀者的尸检组织显示恰恰相反，死亡人数增加 Gsα 的比例集中在脂筏中，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，几种迷幻或解离麻醉化合物可能具有抗抑郁作用，例如 以及更短的治疗开始时间，拟议的研究将寻找细胞“生物特征” 抗抑郁作用。拟议的研究还将尝试建立对 Gsα 从脂筏上的易位是抑郁症的标志，也是抗抑郁作用的渠道。 拟议研究的一个目的是开发一个平台，可以为假定的细胞提供基于细胞的筛选 抗抑郁化合物以及指示个性化抗抑郁药物选择的筛选工具。其他 这些研究的目的是提供抑郁症的外周组织生物标志物以及早期（< 1 周） 抗抑郁治疗成功的指标，可以开发成临床上有用的、廉价的和 可供临床使用的现成生物标志物。抗抑郁作用途径的确定可能会导致 新型抗抑郁药物，而为抑郁症指定一个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。

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