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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：
8940469
负责人：
MARK M. RASENICK
金额：
$ 23.97万
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/8940469
关键词：
Acylation Adenylate Cyclase Aftercare 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 GTP-Binding Proteins Goals Human Image In Vitro Individual Investigation Ketamine Liquid substance Location Major Depressive Disorder Marketing 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 Patients Peripheral Pharmaceutical Preparations Phenotype Placebos Population Property Recording of previous events Relative (related person)Reporting Risk Sampling Selective Serotonin Reuptake Inhibitor Severities Signal Transduction Speed Suggestion Supplementation System Testing Therapeutic Time Tissues Translating Treatment Efficacy Unsaturated Fatty Acids Work base biosignature cellular imaging clinical efficacy cost depressed patient design in vivo innovation lymphoblast novel pre-clinical preclinical study predictive modeling public health relevance research study 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.