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（由适用提供）：假设G蛋白GS与脂质筏相关的程度是抑郁症和治疗反应的指标。最初的观察结果表明，这种生物签名是在验尸组织中进行的，我们已经通过体内和体外的初步数据扩展了这项工作，这表明由简单检测器提取确定的GS定位，是N-3 PUFA的建议，即N-3 PUFA具有抗抑郁活性或可以协调某些抗药性药物的抗抑郁活性。为了测试这一点，我们将使用神经胶质细胞系以及来自抑郁症受试者的淋巴母细胞，这些受试者抗抑郁药反应或反应反应。这应该为对抗抑郁药的反应提供预测模型，无论该药物是鱼油，西妥位丙酰胺还是某种组合。我们将通过测量NIMH资助的临床试验中收集的血细胞中GS的脂质筏分布素来测试生物标志物的适用性，以显示N-3 PUFA增强抗抑郁反应的增强。提出的实验还尝试将机械临床前研究与临床研究结合在一起，以提出和测试生物标志物。临床前的工作旨在确定用抗抑郁药±N-3 PUFA将GS转移到质膜的非牛皮级分的情况下，在此是否更有效地激活腺苷酸周期。我们建议一种在富含胆固醇的膜结构域（脂质筏）中具有抗抑郁药浓度的化合物，并破坏了GS在这些结构域内的锚定。为此，一种可能的机制是GS的直接修改。这将通过膜成分的生化分馏，光漂白后的荧光恢复（FRAP）和细胞成像进行研究。由于大多数抗抑郁药治疗（节省氯胺酮）在治疗效率之前需要时间滞后，并且可以在细胞中复制，因此，将使用荧光GS融合蛋白实时监测GS的易位。如果N-3 PUFA单独或与SSRI结合使用抗抑郁活性的这些生物学标志，则可以通过检查N-3 PUFA抗抑郁效率（±SSRIS）的抗抑郁药效率的临床研究来翻译这一点。初始数据从这项研究中，与单独的安慰剂或SSRI相比，对N3 PUFA + SSRI的抗抑郁反应更大。最后，我们将通过生化和成像研究测试淋巴细胞，这些淋巴母细胞来自抑郁症患者，对西妥位酰胺的反应（或缺乏反应）。一个目标是开发一个高内容屏幕，该屏幕可能会表明给定潜在疗法的有效性。成功完成拟议的研究还将表明补充N-3 PUFA对抗抑郁治疗的有用性，以减少发作时间和/或降低总体抗抑郁剂剂量的时间。他们还将为在广泛的药物中建立抑郁症和抗抑郁效率的低成本血液生物标志物铺平道路。