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

Gs 的脂筏定位：抑郁症和治疗反应的生物标志物

• 批准号: 8246317
• 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 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246317
• 关键词: Adenylate Cyclase; Aftercare; Animal Model; Antidepressive Agents; Biological; Biological Markers; Biological Markers; Biological Models; Blood Cells; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; Cell Fraction; Cell Line; Cell membrane; Cells; Chimeric Proteins; Chronic; Citalopram; Clinical; Clinical Research; Coupling; Cultured Cells; Cyclic AMP; Data; Depressed mood; Depression and Suicide; Depressive disorder; Detergents; Development; Diagnosis; Economics; Enrollment; Event; GTP-Binding Proteins; Genetic; Glioma; Heterotrimeric GTP-Binding Proteins; Human; In Vitro; Knowledge; Laboratories; Lead; Left; Life; Link; Lymphocyte; Measurement; Measures; Membrane; Membrane Microdomains; Mental Depression; Methods; Military Personnel; Molecular; Movement; Myocardial Ischemia; Neurons; Neurotransmitters; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phosphorylation; Population; Production; Proteins; Research; Series; Serotonin; Signal Transduction; Site; Solubility; Speed; Suicide; Synapses; System; Testing; Therapeutic; Time; Tissues; Triton X100; Veterans; Work; World Health Organization; base; design; disability; induced pluripotent stem cell; lymphoblast; novel; research study; response; suicide victim; treatment duration; uptake

DESCRIPTION (provided by applicant): Despite several decades of research, 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 pre-synaptic 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 C6 glioma cells with a number of chemically diverse antidepressant compounds translocates the heterotrimeric G protein Gs1 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 Gsa ensconsed in lipid rafts. This study will examine the antidepressant-induced movement of Gs1 out of lipid rafts and the consequences of this for G protein signaling systems. The cells to be examined are lymphoblasts generated from depressed subjects who responded, or did not respond to citalopram (many from the STAR*D study). While these cells are routinely used for genetic studies, we suggest that their use in a cell biological approach to depression and antidepressant action is both novel and with great potential. The extent of Gs1 in lipid rafts will be correlated with both depression ratings and clinical response to antidepressants. Cells will treated directly with antidepressant and will then be analyzed for the amount of Gsa in raft and non-raft membrane compartments both before and during drug treatment. This will be correlated with degree of depression and extent of therapeutic response. Cells will also be examined for downstream consequences of increased cAMP signaling, including activated pCREB and BDNF. Gsa translocation will also be confirmed in living cells expressing a fluorescent Gsa fusion protein. The ratio between raft:non-raft Gsa may prove to be 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. PUBLIC HEALTH RELEVANCE: The burden of depression, both from a societal and economic standpoint, ranks second only to ischemic heart disease. By the year 2020, the World Health Organization projects that depression will be the leading cause of disability worldwide. Depression and suicide are particularly prevalent in military returning from deployment and the population of Veterans they become. We have observed in studies with cultured cells and examination of brains taken from suicide victims with documented depression, that a protein involved in the action of neurotransmitters, such as serotonin, becomes less soluble in the presence of a detergent. We will examine this in blood cells from depressed patients who responded to antidepressants as well as those who didn't. We suggest that the solubility of this protein, known as Gsa, is an easily identified marker for depression as well as therapeutic response, which is available in blood cells. Knowledge gained from this study should help to develop a rapid and inexpensive screen for antidepressant responsiveness, allowing changes in therapy long before the current 4-6 week lag time.

描述(由申请人提供)： 尽管经过了几十年的研究，但对于抗抑郁药物(或抑郁障碍)的分子/细胞作用基础，还没有出现统一的假设。在过去的几年里，我们已经提出，除了突触前靶点(摄取部位)，一些抗抑郁药物还有突触后的作用机制。为此，我们观察到，C6胶质瘤细胞用许多化学上不同的抗抑郁化合物慢性处理(3-5天)后，异三聚体G蛋白GS1从脂筏中移位，并与腺酰环化酶更紧密地结合。抑郁症自杀者的死后组织显示出相反的情况，GSA存在于脂筏中的比例增加。这项研究将研究抗抑郁剂诱导的GS1移出脂筏，以及这对G蛋白信号系统的影响。要检查的细胞是抑郁症受试者产生的淋巴母细胞，这些受试者对西酞普兰有反应或没有反应(许多来自STAR*D研究)。虽然这些细胞通常用于遗传学研究，但我们认为，它们在抑郁症和抗抑郁作用的细胞生物学方法中的使用既新颖又具有巨大的潜力。脂筏中GS1的程度将与抑郁分级和抗抑郁药物的临床反应相关。细胞将直接用抗抑郁剂处理，然后在药物治疗前和药物治疗期间分析RAFT和非RAFT膜室中GSA的量。这将与抑郁的程度和治疗反应的程度相关。还将检查细胞cAMP信号增加的下游后果，包括激活的pCREB和BDNF。GSA易位也将在表达荧光GSA融合蛋白的活细胞中得到证实。RAFT/非RAFT GSA的比值可能被证明是抑郁症的外周组织生物标志物和抗抑郁药物治疗成功的早期(1周)指标，可以发展成为临床上有用、廉价和易于临床使用的生物标志物。 公共卫生相关性： 从社会和经济的角度来看，抑郁症的负担仅次于缺血性心脏病。世界卫生组织预计，到2020年，抑郁症将成为全球残疾的主要原因。抑郁和自杀在从部署归来的军队和他们成为退伍军人的人群中特别普遍。我们在培养细胞的研究和对患有抑郁症的自杀者大脑的检查中观察到，参与神经递质活动的蛋白质，如5-羟色胺，在洗涤剂存在的情况下变得更难溶解。我们将在抗抑郁药物有效和无效的抑郁症患者的血细胞中检测这一点。我们认为，这种蛋白质的溶解性，即GSA，是一个容易识别的抑郁症和治疗反应的标志，这种标志存在于血细胞中。从这项研究中获得的知识应该有助于开发一种快速且廉价的抗抑郁药物反应筛查，允许在目前4-6周的滞后时间之前很久就改变治疗。