Epigenetic modulation of antidepressant efficacy

抗抑郁功效的表观遗传调节

• 批准号: 8582998
• 负责人: CLAUDIA SCHMAUSS
• 金额: $ 24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582998
• 关键词: Acetylation; Adolescence; Adolescent; Adult; Adverse effects; Affect; Antidepressive Agents; Behavior; Behavioral; Biological Markers; Brain; Brain-Derived Neurotrophic Factor; Complex; Development; Diagnosis; Disease; Drug Targeting; Early treatment; Emotional; Environment; Epigenetic Process; Exhibits; Fluoxetine; Genes; Genetic Polymorphism; Genetic Risk; Histone H4; Histones; Individual; Individual Differences; Knockout Mice; Laboratory Study; Lead; Life Stress; Link; Measures; Mediating; Molecular; Mono-S; Monoamine Oxidase Inhibitors; Mood Disorders; Mouse Strains; Mus; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathogenesis; Patients; Peripheral; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Phenotype; Placebos; Prosencephalon; Psychopathology; Receptor Activation; Receptor Signaling; Recording of previous events; Refractory; Risk; Risk Factors; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Severities; Signal Transduction; Stress; Testing; Treatment outcome; Tricyclic Antidepressive Agents; Variant; base; disability; experience; extracellular; frontal lobe; human CCDC6 protein; improved; inhibitor/antagonist; monoamine; novel; patient population; promoter; protein expression; public health relevance; receptor; response; serotonin transporter; symptomatic improvement; tianeptine; treatment effect; treatment response

DESCRIPTION (provided by applicant): Mood disorders are the second leading cause of disability worldwide. Their treatment relies predominantly on antidepressant drugs that target brain monoamines, including selective serotonin-reuptake inhibitors (SSRIs). However, even after the prolonged treatment, the antidepressant effects vary considerably, with only a small faction of patients exhibiting significant treatment effects. Since the pathogenesis of mood disorders is complex, with different contributions of genetic risk, environmental influences, and epigenetic phenotypes in individuals with the same diagnosis, the concept of a more "personalized therapy" is gaining increasing momentum, especially for subjects with a history of early life stress (ELS), a prominent risk factor for mood disorders and one of the strongest predictors of poor treatment response. This exploratory proposal targets the treatment of this population of patients and aims at linking the antidepressant efficacy of SSRIs to the patient's epigenetic phenotype. A recent study from this laboratory showed that a stress-susceptible strain of mice (Balb/c) exposed to ELS exhibits an adaptive epigenetic response to ELS, namely increased acetylation of histone H4 protein in the frontal cortex, that ameliorates the severity of the adult emotional psychopathology associated with ELS exposure. Strikingly, adolescent fluoxetine treatment of ELS Balb/c mice exerted powerful antidepressant effects and further elevated levels of acetylated histone H4 protein. These findings motivated the behavioral and molecular studies on different mouse strains proposed here that test the hypothesis that the effect of fluoxetine on histone H4 acetylation is a critical determinant of antidepressant efficacy and that enhanced serotonergic signaling and reduced activity of histone deacetylases (HDACs) lead to this effect. Studies on ELS Balb/c mice with reduced HDAC activity investigate the role of increased serotonergic signaling in stimulating histone H4 acetylation by comparing the effects of adolescent treatments with antidepressant drugs that either increase serotonin (5-HT) levels in the brain (fluoxetine) or that do not alter them (tianeptine). They also examine the role of 5-HT1A and 5-HT2 receptors as well as the role of brain derived neurotrophic factor-mediated trkB-signaling in mediating this effect. Additional studies on C57Bl/6 serotonin-transporter knockout mice with elevated forebrain 5-HT levels and no response to fluoxetine investigate whether reducing HDAC activity alone is sufficient to elevate histone H4 acetylation and to rescue antidepressant treatment response. Finally, studies on two additional strains of mice with low responsiveness to fluoxetine test whether co-treatment with fluoxetine and an HDAC inhibitor enhances antidepressant effects, and whether reducing HDAC activity during adolescence or adulthood has the same effect on histone H4 acetylation and antidepressant treatment response. In all studies, the possibility that drug-induced changes in histone H4 acetylation in brain are also found in peripheral blood lymphocytes will be explored. Positive results from these studies could identify a new biomarker capable of predicting antidepressant treatment response.

描述（由申请人提供）：情绪障碍是全球第二大致残原因。他们的治疗主要依赖于针对大脑单胺的抗抑郁药物，包括选择性血清素再摄取抑制剂（SSRIs）。然而，即使在长期治疗后，抗抑郁效果也有很大差异，只有一小部分患者表现出显著的治疗效果。由于情绪障碍的发病机制是复杂的，具有相同诊断的个体具有不同的遗传风险，环境影响和表观遗传表型，因此更加“个性化治疗”的概念正在获得越来越多的动力，特别是对于具有早期生活应激史（ELS）的受试者，ELS是情绪障碍的重要危险因素之一，也是治疗反应不良的最强预测因素之一。这一探索性建议针对这类患者的治疗，旨在将SSRIs的抗抑郁疗效与患者的表观遗传表型联系起来。该实验室最近的一项研究表明，暴露于ELS的应激易感小鼠（Balb/c）表现出对ELS的适应性表观遗传反应，即额叶皮层组蛋白H4蛋白乙酰化增加，从而改善了ELS的严重程度