Immune Activation, Cerebral Metabolic Activity and Depression in Treated HIV-Infection

项目摘要 抑郁症是一个严重的医学挑战，影响着数百万患有抑郁症的人的发病率。 尽管有有效的抗逆转录病毒疗法（ART），艾滋病毒仍然存在。抑郁症患者亚组 这些疾病对传统的抗抑郁治疗没有反应，可能反映了疾病 标准疗法无法解决的机制。这一多学科的建议旨在了解 宿主因子与神经功能之间的相互作用通过识别代谢途径 使用新的高通量代谢物分析结合神经成像， 免疫学研究 K23指导临床科学家研究职业发展奖详细介绍了 全面的五年计划，让候选人获得正式的培训和指导， 在高级计算建模，免疫和宿主防御方面的专业知识。在K23 建议，候选人将在随机， 在HIV感染者中进行的双盲、安慰剂对照试验。首先，候选人的目标是学习 2- [18F]-氟脱氧葡萄糖正电子发射断层扫描（PET）脑功能成像 (FDG)，神经活动的敏感指标，并将确定与免疫细胞标志物的关系， 萧条其次，候选人寻求确定单核细胞亚群的影响， 活化的T淋巴细胞对慢性HIV感染治疗后抑郁症的影响第三，通过研究血液 HIV感染者抑郁症代谢组的横断面分析与验证 研究结果在一个独立的纵向队列，候选人将了解如何系统的副产品， 代谢途径可用于识别艾滋病毒感染者谁是“风险”持续 抑郁症状 在获奖过程中，候选人将探索全身代谢途径 影响接受ART的HIV感染成人的抑郁症，目的是确定潜在的新的 诊断和治疗目标。候选人是一个委员会认证的神经科医生， 分子生物学和神经科学方面的培训。为了为独立的研究生涯做准备， 候选人将完成生物信息学分析大规模数据集和免疫学的培训 通过课程和临床，生物和代谢数据的分析，从 神经亚组研究和多个现有慢性HIV感染队列。候选人的培训 将由艾滋病毒感染领域的资深导师和高级顾问委员会指导， 在艾滋病相关神经发病机制和代谢疾病方面具有集体专业知识的科学家， 代谢组学、计算建模、生物信息学、生物统计学和神经成像。

Project Summary Depression is a critical medical challenge affecting the morbidity of millions of people living with HIV despite availability of effective antiretroviral therapy (ART). Subsets of patients with depressive disorders do not respond to traditional antidepressant treatments, potentially reflecting disease mechanisms not addressed with standard therapy. This multidisciplinary proposal seeks to understand the interactions between host factors and neurological function by identifying metabolic pathways altered in depression using novel high-throughput metabolite profiling coupled with neuroimaging and immunological studies. This K23 Mentored Clinical Scientist Research Career Development Award details a comprehensive five-year program for the candidate to acquire formal training and mentorship with specific expertise in advanced computational modeling, and immunity and host defense. In this K23 proposal, the candidate will carry out a neurological substudy within the framework of a randomized, double-blind, placebo controlled trial in participants with HIV infection. First, the candidate aims to study cerebral function by positron emission tomography (PET) imaging with 2- [18F]-fluorodeoxyglucose (FDG), a sensitive indicator of neural activity and will define relationships with immune cell markers and depression. Second, the candidate seeks to determine the influence of monocyte subsets and activated T-lymphocytes on depression in treated chronic HIV-infection. Third, by studying the blood metabolome from HIV-infected individuals with depression in cross-sectional analysis and validating findings in an independent longitudinal cohort, the candidate will learn how systemic byproducts of metabolic pathways may be used to identify people living with HIV who are “at risk” for persistent depressive symptoms. During the course of the award, the candidate will explore systemic metabolic pathways influencing depression in HIV-infected adults on ART with the goal of identifying potential novel diagnostic and therapeutic targets. The candidate is a board-certified neurologist with prior doctoral training in molecular biology and neuroscience. In preparation for an independent research career, the candidate will complete training in bioinformatics for analyzing large-scale datasets, and immunology through coursework and analysis of clinical, biological and metabolite data derived from the neurological substudy and multiple existing cohorts with chronic HIV infection. The candidate’s training will be guided by established mentors in the field of HIV infection and an advisory committee of senior scientists with collective expertise in HIV-associated neuropathogenesis and metabolic disease, metabolomics, computational modeling, bioinformatics, biostatistics, and neuroimaging.