Mechanism of Action for n-3 PUFA antidepressant properties

n-3 PUFA 抗抑郁特性的作用机制

基本信息

批准号：
9334112
负责人：
MARK M. RASENICK
金额：
$ 40.29万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2019-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334112
关键词：
Acylation Adenylate Cyclase Aftercare Alpha Cell Animal Model Antidepressive Agents Autopsy Biochemical Biological Biological Assay Biological Markers Biological Models Blood Blood Cells Blood Platelets Blood Tests Cell Line Cell membrane Cells Chemosensitization Chimeric Proteins Cholesterol Chronic Citalopram Clinical Clinical Research Clinical Trials Cultured Cells Data Depressed mood Detergents Development Dietary Supplementation Disease Dose Drug Exposure Effectiveness Enrollment Environment Erythrocytes Etiology Evaluation Exposure to Fish Oils Fluorescence Recovery After Photobleaching Foundations Fractionation Funding G-substrate GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Goals Human In Vitro Individual Investigation Ketamine Liquid substance Location Major Depressive Disorder Measures Mediating Membrane Membrane Lipids Membrane Microdomains Mental Depression Modification Monitor N-3 polyunsaturated fatty acid National Institute of Mental Health Neuroglia Omega-3 Fatty Acids Peripheral Pharmaceutical Preparations Phenotype Placebos Population Property Recording of previous events Reporting Risk Sampling Selective Serotonin Reuptake Inhibitor Severities Signaling Protein Speed Suggestion Supplementation System Testing Therapeutic Time Tissues Translating Treatment Efficacy Unsaturated Fatty Acids Work antidepressant effect base biosignature cellular imaging clinical efficacy cost depressed patient design experimental study imaging study in vivo individual patient innovation lymphoblast novel pre-clinical preclinical study predictive modeling prospective public health relevance response screening time use treatment response

项目摘要

DESCRIPTION (provided by applicant): It is hypothesized that the degree to which the G protein, Gs, is associated with lipid rafts is an indicator of both depression and therapeutic response. The original observations suggesting this biosignature were made in postmortem tissue, and we have extended this work with in vivo and in vitro preliminary data suggesting that raft localization of Gs, determined by simple detergent extraction, is a biomarker of both depression and antidepressant response. There are suggestions that n-3 PUFA either have antidepressant activity or can synergize the action of some antidepressant drugs. To test this, we will use a glial cell line as well as lymphoblasts from depressed subjects who were either antidepressant responsive or unresponsive. This should provide a predictive model for the response to an antidepressant agent, whether that agent is fish oil, citalopram, or some combination. We will test the applicability of the biomarker by measuring the lipid raft distributin of Gs in membranes from blood cells collected during an NIMH-funded clinical trial showing n-3 PUFA augmentation of antidepressant response. The proposed experiments also attempt to mesh mechanistic preclinical studies with a clinical study to propose and test a biomarker. The preclinical work seeks to determine whether in-vitro treatment with antidepressants ± n-3 PUFA shifts Gs into non-raft fractions of the plasma membrane, where it more effectively activates adenylyl cyclase. We suggest that a compound with antidepressant efficacy concentrates in cholesterol-rich membrane domains (lipid rafts) and disrupts the anchoring of Gs within those domains. One possible mechanism for this is direct modification of Gs. This will be studied by biochemical fractionation of membrane components, fluorescence recovery after photobleaching (FRAP) and by cellular imaging. Since most antidepressant therapy (save ketamine) requires a time lag prior to therapeutic efficacy and this can be replicated in cells, translocation of Gs in response to antidepressant agents will be monitored in real time using a fluorescent Gs fusion protein. Should n-3 PUFA show these biological hallmarks of antidepressant activity, alone or in combination with SSRIs , this will be translated by examining blood taken in a clinical study of the antidepressant efficacy of n-3 PUFA (± SSRIs). Initial data from this study show a greater antidepressant response to n3 PUFA + SSRI than to placebo or SSRI alone. Finally, we will test, with the biochemical and imaging studies, lymphoblasts, derived from depressed patients with known response (or lack thereof) to citalopram. One goal is to develop a high content screen that might suggest, prospectively, the effectiveness of a given potential therapy. Successful completion of the proposed studies will also indicate the usefulness of n-3 PUFA supplementation to antidepressant therapy for decreasing time of therapeutic onset and/or lowering overall antidepressant dose. They will also pave the way toward establishing a low-cost blood biomarker for both depression and antidepressant efficacy over a broad range of agents.

描述（由申请人提供）：G 蛋白 Gs 与脂筏的关联程度是抑郁症和治疗反应的指标，最初的观察表明这种生物印记是在死后组织中进行的，并且我们用体内和体外初步数据扩展了这项工作，表明通过简单的洗涤剂提取确定的 Gsα 的筏定位是抑郁和抗抑郁反应的生物标志物。有人建议 n-3。 PUFA 具有抗抑郁活性，或者可以协同某些抗抑郁药物的作用，为了测试这一点，我们将使用来自抗抑郁药物有反应或无反应的抑郁受试者的淋巴母细胞。对于抗抑郁药，无论该药物是鱼油、西酞普兰还是某些组合，我们将通过测量脂筏分布来测试生物标志物的适用性。 NIMH 资助的一项临床试验中收集的血细胞膜中的 Gs 显示 n-3 PUFA 增强了抗抑郁反应。拟议的实验还试图将临床前研究与临床研究结合起来，以提出并测试临床前工作所寻求的生物标志物。确定抗抑郁药 ± n-3 PUFA 的体外治疗是否会将 Gs 转移到质膜的非筏部分，从而更有效地激活我们建议具有抗抑郁功效的化合物集中在富含胆固醇的膜结构域（脂筏）中，并破坏这些结构域中 Gsα 的锚定，这将通过直接修饰 Gsα 进行研究。膜成分的生化分级、光漂白后的荧光恢复 (FRAP) 以及细胞成像，因为大多数抗抑郁疗法（除了氯胺酮）在发挥疗效之前需要一段时间的延迟。这可以在细胞中复制，如果 n-3 PUFA 单独或与 SSRI 联合使用，将使用荧光 Gs 融合蛋白实时监测抗抑郁药物反应中的 Gs 易位。这将通过检查 n-3 PUFA 抗抑郁功效临床研究中采集的血液来转化（± SSRIs 初始数据）。这项研究表明，n3 PUFA + SSRI 的抗抑郁反应比安慰剂或单独 SSRI 的反应更大。最后，我们将通过生化和影像学研究，测试来自对西酞普兰已知反应（或缺乏反应）的抑郁症患者的淋巴母细胞。一个目标是开发一种高内涵筛选，可以前瞻性地表明给定潜在疗法的有效性，成功完成拟议的研究也将表明补充 n-3 PUFA 对抗抑郁疗法的有用性。缩短治疗起效时间和/或降低总体抗抑郁药剂量，它们还将为建立低成本血液生物标志物铺平道路，以评估多种药物的抑郁症和抗抑郁功效。