Allopregnanolone and Gamma-Aminobutyric Acid Receptor (GABA-A-R) Plasticity in Women with Premenstrual Mood Symptoms

四氢孕酮和 γ-氨基丁酸受体 (GABA-A-R) 可塑性对有经前情绪症状的女性

• 批准号: 10363837
• 负责人: Liisa Victoria Hantsoo
• 金额: $ 25.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363837
• 关键词: Affect; Allopregnanolone; Animal Model; Anxiety; Blood; Brain Diseases; Characteristics; Chicago; Clinical; Clinical Trials; Communities; Complement; Control Groups; Data; Drops; Functional disorder; Future; GABA Agonists; GABA Receptor; Generalized Anxiety Disorder; Goals; Gold; Hormonal; Hormones; Human; Illinois; Impairment; Light; Literature; Luteal Phase; Mass Fragmentography; Measures; Menstrual cycle; Menstruation; Methodology; Methods; Mood Disorders; Morbidity - disease rate; National Institute of Mental Health; Outcome Measure; Panic Disorder; Participant; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Polymerase Chain Reaction; Population; Prevalence; Progesterone; Prospective Studies; Research; Research Personnel; Rodent; Rodent Model; Role; Scientist; Selective Serotonin Reuptake Inhibitor; Severities; Statistical Models; Steroids; Structure; Symptoms; System; Techniques; Testing; Time; Universities; Withdrawal; Woman; Work; antagonist; anxiety-like behavior; base; clinically significant; depressive symptoms; experience; external ear auricle; gamma-Aminobutyric Acid; mood symptom; neurosteroids; novel; novel marker; personalized medicine; phase change; pre-clinical; premenstrual dysphoric disorder; proliferative phase Menstrual cycle; prospective; receptor; recruit; reproductive; response; therapy development; treatment response

PROJECT SUMMARY Roughly 20% of women experience clinically significant anxiety, irritability, or depressive symptoms in the premenstrual (luteal) phase of the menstrual cycle. This includes premenstrual dysphoric disorder (PMDD), a severe affective disorder impacting millions of women worldwide. Despite this morbidity, research on PMDD’s pathophysiology lags behind that of other brain disorders. A potential contributor to PMDD’s pathophysiology is allopregnanolone (ALLO), a progesterone metabolite and powerful GABA-A receptor (GABA-A-R) modulator that fluctuates across the luteal phase. Importantly, rodent models of PMDD indicate impaired GABA-A-R plasticity in response to ALLO fluctuations. Building on this preclinical literature and clinical findings from the PI’s K23 (NIMH K23MH107831), the proposed research will test the hypothesis that rapid ALLO changes across the luteal phase, in interaction with suboptimal GABA-A-R receptor subunit reconfiguration, contribute to premenstrual mood symptoms. We will assess 67 women with regular menstrual cycles (33 controls, 34 with premenstrual dysphoric disorder (PMDD)) based on the gold standard Daily Record of Severity of Problems. We will capture two outcome measures: 1) We will measure plasma ALLO changes within subjects at multiple timepoints across the luteal phase using precise gas chromatography/mass spectrometry (GC/MS) methods. 2) We will use a novel biomarker, GABA-A-R subunit expression in peripheral blood mononuclear cell (PBMCs) measured via real-time polymerase chain reaction (RT-qPCR), to examine GABA-A-R subunit expression across the luteal phase. We hypothesize that controls and women with PMDD will differ in luteal phase decline in ALLO levels (e.g. controls will have a more gradual decline), and will differ in GABA-A-R subunit expression as ALLO levels decline. Combining these powerful methodologies will enable us to examine a mechanistic hypothesis about ALLO dynamics and GABA-A-R plasticity in women with premenstrual mood symptoms, in a prospective within-subject manner. The investigators bring complementary expertise; Dr. Hantsoo in prospectively studying women with PMDD, and Dr. Pinna in applying state-of-the-art methods to study the impact of ALLO on GABA-A-R function. This study represents a critical step in elucidating ALLO - GABA-A-R dynamics in this population, and will lead to an R01 that examines ALLO - GABA-A-R dynamics in women with PMDD when treated with selective serotonin reuptake inhibitors (SSRIs). Understanding PMDD’s pathophysiology may inform treatment development; only 60% of women with PMDD respond to the first-line treatment (SSRIs), and new GABA-modulating drugs are being developed (e.g. brexanolone and sepranolone, GABA-A modulating steroid antagonists). Before meaningful work is done in treatment development and personalized medicine in PMDD, mechanisms such as ALLO - GABA-A-R dynamics must be clarified.

项目摘要 大约20％的女性在临床上具有重要的动画，易怒或抑郁症状 月经周期的经前（黄体）阶段。这包括经前烦躁不安（PMDD），一个 受到严重影响的疾病，影响了全球数百万妇女。尽管有这种发病率，但对PMDD的研究 病理生理落后于其他脑疾病。 PMDD病理生理学的潜在贡献者是 Allopregnanolone（Allo），孕酮代谢物和强大的GABA-A受体（GABA-A-R）调节剂 这在整个黄体期波动。重要的是，PMDD的啮齿动物模型表明GABA-A-R受损 响应Allo波动的可塑性。以这种临床前文献和临床发现为基础 PI的K23（NIMH K23MH107831），拟议的研究将检验以下假设，即快速Allo改变 在整个黄体阶段，与次优的GABA-A-R受体亚基重新配置的相互作用， 导致经前情绪症状。我们将评估67名常规月经周期的妇女（33个 对照，34具有经前烦躁不安（PMDD）），基于金标准的每日记录 问题的严重程度。我们将捕获两种结果指标：1）我们将测量血浆allo变化 使用精度气相色谱/质量，在整个黄体期的多个时间点内的受试者内部 光谱法（GC/MS）方法。 2）我们将在外围使用一种新型的生物标志物GABA-A-R亚基表达 通过实时聚合酶链反应（RT-QPCR）测量的血液单核细胞（PBMC），以检查 整个黄体期的GABA-A-R亚基表达。我们假设控制PMDD的控制和女性 Allo水平的黄体期下降会有所不同（例如，对照将有更高的下降），并且会有所不同 随着Allo水平下降，GABA-A-R亚基表达中的表达。结合这些强大的方法将启用 我们要检查有关女性的机械假设 经过前瞻性的内部症状。调查人员带来完整的 专业知识; Hantsoo博士前瞻性地研究PMDD的女性，Pinna博士应用最先进的 研究Allo对GABA-A-R功能的影响的方法。这项研究代表了阐明的关键步骤 Allo-GABA-A-R动力学在该人群中，并将导致R01检查Allo-GABA-A-R 用选择性5-羟色胺再摄取抑制剂（SSRIS）治疗PMDD女性的动力学。 了解PMDD的病理生理可能会为治疗发展提供依据；只有60％的PMDD女性 对一线治疗（SSRI）的反应，并开发了新的GABA调节药物（例如， Brexanolone和Sepranolone，GABA-A调节类固醇拮抗剂）。在有意义的工作之前 PMDD中的治疗开发和个性化医学，诸如Allo-gaba-a-r之类的机制 必须澄清动力。