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

体内靶向神经活性类固醇和免疫网络治疗艾滋病毒感染者的抑郁症。

基本信息

批准号：
10701054
负责人：
Shibani Sharon Mukerji
金额：
$ 75.59万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-08 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10701054
关键词：
Address Adult Affect Analgesics Animal Model Anti-Anxiety Agents Antidepressive Agents Automobile Driving B-Lymphocytes Behavior Behavioral Biological Biological Markers Biology Blood Brain Cells Cessation of life Chemicals Cholesterol Chronic Clinical Collaborations Corpus striatum structure Data Depressed mood Disease Disease remission Double-Blind Method Double-blind trial Elements Emotional Enrollment Functional Magnetic Resonance Imaging Functional disorder Gene Expression Profile Genes Genetic Transcription HIV HIV Infections Human Immune Immune response Immune system Immunology Inflammation Inflammation Mediators Inflammatory Infrastructure Interferons Interneurons Knowledge Laboratories Lead Left Magnetic Resonance Spectroscopy Measurement Mediating Mental Depression Modeling Mood Disorders Multi-Institutional Clinical Trial Nervous System Physiology Neuropathogenesis Neuropsychology Neurosecretory Systems Neurotransmitters Oral Pathogenesis Pathogenicity Pathology Pathway interactions Peripheral Persons Phenotype Placebos Population Positioning Attribute Pregnenolone Prevalence Property Randomized Reaction Time Receptor Signaling Research Personnel Risk Factors Severities Site Supplementation T-Lymphocyte Testing Therapeutic Toll-like receptors antiretroviral therapy behavioral response biological adaptation to stress chronic pain clinical predictors cohort depressive symptoms design disability epidemiology study financial incentive gamma-Aminobutyric Acid hypothalamic-pituitary-adrenal axis improved in vivo inflammatory marker insight modifiable risk monocyte neural neuroimaging neurosteroids neurotoxicity neurotransmission new therapeutic target novel placebo controlled trial preclinical study predict clinical outcome responders and non-responders response reward expectancy screening steroid hormone systemic inflammatory response trial enrollment

项目摘要

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.

项目概要尽管艾滋病毒感染者 (PLWH) 的抑郁症患病率估计为 20-45% 三分之二的成年人的抗逆转录病毒治疗未得到充分治疗，只有三分之一的成年人达到了预期目标缓解。下丘脑-垂体-肾上腺轴功能障碍和慢性炎症导致 PLWH 中的抑郁症状代表了靶向的替代途径。神经活性类固醇可以改善精神疾病的抑郁症状，并对慢性疼痛有效。在人类研究表明，这种效应是由孕烯醇酮介导的，孕烯醇酮是第一种源自胆固醇的神经活性类固醇。在这个提议中，我们假设神经心理疾病发病机制的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感染者。神经活性类固醇的变化通过多种方式促进神经功能，包括增加 GABA 能神经传递并减少全身炎症。为了解决我们的假设，我们将进行一项 3:1 双盲试验，招募 120 名患有抑郁症的 ART 艾滋病患者，随机接受孕烯醇酮或安慰剂作为附加治疗，为期 8 周，并将系统地研究与抑郁症相关的 GABA 介导的抑制和外周免疫反应情绪。该项目利用磁共振波谱和基于任务的功能磁共振成像来探测孕烯醇酮后的行为和神经反应。我们将纵向分析免疫细胞群并研究单核细胞的转录反应识别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以预测接受治疗的 PLWH 的临床改善孕烯醇酮。该提案利用了广泛的神经影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。我们的方法可能定义孕烯醇酮与抑郁症机制之间的新关系，可能表明基于神经活性类固醇生物学的新治疗目标，以解决未满足的关键需求感染者。