In Vivo Targeting of Neuroactive Steroid and Immune Networks for Depression in People Living with HIV.

项目摘要 艾滋病毒感染者（PLWH）的抑郁症患病率估计为20 - 45%， 三分之二的成年人没有得到充分的抗逆转录病毒治疗，只有三分之一的成年人 缓解。下丘脑-垂体-肾上腺轴功能障碍和慢性炎症有助于 抑郁症状的PLWH和代表替代途径的目标。神经活性类固醇 可以改善精神疾病中的抑郁症状，对慢性疼痛有效。人 研究表明，这种作用是由胆固醇衍生的第一种神经活性类固醇- 在这个建议中，我们假设神经心理疾病的发病机制是一个中心机制， 是神经活性类固醇的相对缺乏，定义了抑郁情绪的生物亚型， PLWH。神经活性类固醇的变化通过几种方式促进神经功能，包括 增加GABA能神经传递和减少全身炎症。解决我们 假设，我们将进行一项3：1的双盲试验，招募120名患有抑郁症的ART患者， 随机分配至双烯醇酮或安慰剂，作为添加治疗，持续8周，并将系统地 研究GABA介导抑制和外周免疫反应与抑郁症的关系 心情该项目利用磁共振波谱和基于任务的功能磁共振成像技术， 共振成像，以探测行为和神经反应后，去甲烯醇酮。我们将 纵向分析免疫细胞群体并研究单核细胞中的转录反应 来鉴定与临床反应相关的基因。最后，我们将使用基线预测器来建模 神经活性类固醇水平是否可预测接受PLWH治疗的患者的临床改善 去甲烯醇酮该提案利用了广泛的神经成像和免疫分析基础设施 以及合作研究人员和实验室的广泛科学专业知识。我们的方法可能会 定义新的关系之间的烯醇酮和抑郁症的机制，可能表明 基于神经活性类固醇生物学的新治疗靶点，以解决 PLWH。

Project Summary The prevalence of depression in people living with HIV (PLWH) is estimated at 20-45% despite antiretroviral therapy with two-thirds of adults inadequately treated, and only one-third of adults achieving remission. Hypothalamic-pituitary-adrenal axis dysfunction and chronic inflammation contribute to depressive symptoms in PLWH and represent alternative pathways for targeting. Neuroactive steroids can improve depressive symptoms in psychiatric conditions and are effective in chronic pain. In human studies, the effect was mediated by pregnenolone, the first neuroactive steroid derived from cholesterol. In this proposal, we hypothesize that a central mechanism of pathogenesis in neuropsychological disease is a relative deficiency of neuroactive steroids that defines a biological subtype of depressed mood in PLWH. Changes in neuroactive steroids promote neurological functioning by several means that include increasing GABAergic neurotransmission and reducing systemic inflammation. To address our hypothesis, we will perform a 3:1 double-blind trial enrolling 120 PLWH on ART with depression, randomized to pregnenolone or placebo, as add-on therapy, for 8 weeks, and will systematically investigate GABA-mediated inhibition and peripheral immune responses as they relate to depressed mood. This project utilizes magnetic resonance spectroscopy and task-based functional magnetic resonance imaging to probe the behavioral and neural responses after pregnenolone. We will longitudinally profile immune cell populations and investigate the transcriptional responses in monocytes to identify genes associated with clinical response. Finally, we will use baseline predictors to model whether levels of neuroactive steroids predict clinical improvement among PLWH receiving pregnenolone. This proposal leverages an extensive neuroimaging, and immune profiling infrastructure and the extensive scientific expertise of collaborating investigators and laboratories. Our approach may define novel relationships between pregnenolone and mechanisms of depression, potentially suggesting new therapeutic targets based on the biology of neuroactive steroids, to address a critical unmet need in PLWH.