Using Systems Immunology to Get at the Nature of Mood Disorders in HIV

项目摘要 本申请中的建议将利用系统生物学方法来获得潜在的发病机制， 情绪障碍，包括重度抑郁症（MDD）、双相情感障碍（BD）、重度抑郁症合并 接受抗逆转录病毒治疗病毒学抑制的HIV（PWH）感染者中的广泛性焦虑症（GAD） （ART）。过度的目标是1）确定共同和情绪障碍特异性基因表达 根据以下指标，与症状的存在和严重程度相关的抗逆转录病毒治疗的PWH特征 使用比较全血转录组学分析进行心理健康的计算机化自适应测试， 仔细考虑并发GAD和/或既往儿童期创伤; 2）验证和机械解剖 利用靶向ART治疗PWH中MDD、BD和MDD伴GAD的转录组学和代谢组学特征 流式细胞术和代谢组学，以验证差异富集的基因和途径;以及3）重要的是， 通过应用一种新的算法，药物， 干扰基因集富集分析，以鉴定表型相关的、FDA批准的和 可重复使用的治疗方法是治疗伴有情绪障碍的PWH的潜在新治疗选择。完成 为了解决这些复杂的问题，一个专家小组已经组建了一个计划， 招募一组接受ART治疗的病毒学抑制的PWH患者，分为5组：1）MDD，2）BD，3）MDD和GAD，4） GAD，以及5）没有心理健康诊断。该队列将随访24周，并收集数据 对于情绪障碍的存在和严重程度的转录组学、代谢组学和流式细胞术反应， 症状

Project Abstract The proposal in this application will utilize systems biology approaches to get at the underlying pathogenesis of mood disorders including major depressive disorder (MDD), bipolar disorder (BD), MDD combined with generalized anxiety disorder (GAD) in people with HIV (PWH) virologically-suppressed on antiretroviral therapy (ART). The overreaching goals are 1) to identify both common and mood disorder-specific gene expression signatures in PWH on ART that correlate with the presence and severity of symptoms according to computerized adaptive testing for mental health using comparative whole blood transcriptomic analysis while carefully considering concurrent GAD, and/or prior childhood trauma; 2) to validate and mechanistically dissect transcriptomic and metabolomic signatures of MDD, BD, and MDD with GAD in PWH on ART utilizing targeted flow cytometry and metabolomics to validate differentially enriched genes and pathways; and 3) importantly, to find therapeutics that could potentially reverse dysregulated pathways by applying a novel algorithm, drug perturbation gene set enrichment analysis, to identify phenotypically-relevant, FDA-approved and repurposeable therapeutics as potential novel treatment options for PWH with mood disorders. To complete the experiments and answer these complex questions, an expert team has been assembled with the plan to recruit a cohort of PWH virologically suppressed on ART in five groups: 1) MDD, 2) BD, 3) MDD and GAD, 4) GAD, and 5) no mental health diagnoses. This cohort will be followed for 24 weeks and data will be collected for transcriptomic, metabolomic and flow cytometric responses to the presence and severity of mood disorder symptoms.