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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：
10535147
负责人：
Shibani Sharon Mukerji
金额：
$ 82.26万
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/10535147
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 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 base 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 neuroimaging neurosteroids neurotoxicity neurotransmission new therapeutic target novel placebo controlled trial preclinical study predict clinical outcome relating to nervous system response reward expectancy screening steroid hormone systemic inflammatory response

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.

项目总结