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

项目摘要 本申请中的提议将利用系统生物学的方法来获得潜在的发病机制 情绪障碍包括重度抑郁障碍(MDD)、双相情感障碍(BD)、MDD合并 病毒抑制的HIV(PWH)患者的广泛性焦虑症(GAD)--抗逆转录病毒治疗 (艺术)。超乎寻常的目标是：1)识别常见的和心境障碍相关的基因表达 与症状的存在和严重程度相关的抗逆转录病毒治疗的威尔斯亲王的签名 比较全血转录分析在心理健康计算机适应性测试中的应用 仔细考虑并发的GAD和/或既往的童年创伤；2)验证和机械解剖 利用靶向ART技术在PWH中检测MDD、BD和MDD伴GAD的转录和代谢特征 流式细胞术和代谢组学，以验证差异丰富的基因和途径；以及3)重要的是， 通过应用一种新的算法--药物，找到可能逆转失调通路的治疗方法 扰动基因集浓缩分析，以确定表型相关、FDA批准和 可重复利用的治疗方法作为治疗慢性阻塞性肺疾病伴情绪障碍的潜在新选择。要完成 并回答了这些复杂的问题，已经组建了一个专家团队，计划 招募一组在ART上病毒学抑制的PWH队列：1)MDD，2)BD，3)MDD和GAD，4) GAD，以及5)没有精神健康诊断。这一队列将被跟踪24周，并将收集数据 转录、代谢学和流式细胞术对情绪障碍的存在和严重程度的反应 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.