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 艾滋病毒，尽管有有效的抗逆转录病毒治疗(ART)。抑郁症患者的亚群 障碍对传统的抗抑郁药物治疗没有反应，可能反映了疾病 未用标准疗法解决的机制。这项多学科的提案试图理解 通过确定代谢途径研究宿主因素与神经功能之间的相互作用 使用新的高通量代谢物分析结合神经成像和 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 为候选人提供全面的五年计划，以获得正式培训和指导 在高级计算建模、免疫力和宿主防御方面的专门知识。在这K23中 建议，候选人将在一个随机的， HIV感染者的双盲、安慰剂对照试验。首先，候选人的目标是学习 2-[18F]-氟代脱氧葡萄糖正电子发射断层扫描脑功能研究 (FDG)，神经活动的敏感指标，并将定义与免疫细胞标记物和 抑郁症。其次，候选人试图确定单核细胞亚群和 活化T淋巴细胞对慢性HIV感染患者抑郁的影响。第三，通过研究血液 HIV感染者抑郁患者代谢组的横断面分析与验证 在独立的纵向队列中的发现，候选人将学习如何系统性的副产品 新陈代谢途径可能被用来识别艾滋病毒携带者是否有持续感染的风险 抑郁症状。 在获奖过程中，候选人将探索全身代谢途径 ART对HIV感染成人抑郁的影响，目的是确定潜在的新疗法 诊断和治疗目标。应聘者是一名获得董事会认证的神经科医生，拥有博士学位。 分子生物学和神经科学方面的培训。在为独立研究事业做准备的过程中， 应聘者将完成分析大规模数据集的生物信息学和免疫学方面的培训 通过课程作业和对临床、生物和代谢物数据的分析，这些数据来自 神经学亚研究和慢性艾滋病毒感染的多个现有队列。应聘者的训练 将由艾滋病毒感染领域的知名导师和高级顾问委员会指导 在艾滋病毒相关神经发病机制和代谢性疾病方面拥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.