Immunometabolicgene expression profiles associated with depressed mood and behavioral domains inpeople with HIV

摘要 这个项目将利用关于免疫代谢在糖尿病的病理生理学中的作用的新知识。 艾滋病病毒携带者的抑郁，以产生关于未来潜在治疗的假设。威斯康星医院的抑郁症 其特点是与未感染艾滋病毒的人的抑郁症(PWoH)不同。第一个是 快感缺乏的优势--无法从活动中获得乐趣。第二个是更高的患病率 在PWH和PWoH中，对标准抗抑郁药物治疗有抵抗力的抑郁症。这些 临床观察不仅表明抑郁症的潜在病理生理学不同于 这两个人群，但需要不同的治疗方法才能成功地治疗PWH抑郁症。 免疫代谢的分子研究，定义为免疫和代谢之间的相互作用 与PWH中的抑郁症相关的调节失调的基因，支持这些区别。根据我们的初步调查 数据和文献中，我们建议进行RNA-Seq转录，相关的免疫代谢 基因表达对免疫代谢的蛋白质和其他生物标记物、临床抑郁症以及 受抑郁影响的认知过程。我们的假设驱动的方法将专注于两个相互作用的、 共同调节的基因通路是抑郁症和免疫代谢的核心，哺乳动物的靶点是 雷帕霉素(MTOR)和NLRP3炎症体。我们会研究80名新入职的威尔斯亲王医院和40岁- 匹配的PWoH。考虑到我们早期的工作表明免疫代谢和 抑郁症是性别依赖的，我们的目标是男性和绝经前女性各占一半，以便 检查这些关系中的性别差异。为了优化抑郁症状严重程度的频谱， 我们的样本(例如，避免过度代表具有轻微抑郁症状的个人)，我们将分层 在之前建立的Beck Depression Inventory-II Cut-Score上和下面各有一半的细分 用于临床上显著的抑郁症状(≥16)。因为临床研究不能严格地确定 机制关系，我们将并行研究mTOR和NLRP3炎症小体信号在 HIV感染的小鼠模型EcoHIV的抑郁样行为，表达九个关键中的七个 人类艾滋病毒蛋白质。这些通路将使用mTOR和NLRP3抑制剂进行解剖。另外，在这些 我们将描述脑组织中免疫代谢标志物的特征，可能是脑组织的底物 抑郁症。

SUMMARY This project will leverage emerging knowledge about the role of immunometabolism in the pathophysiology of depression in people with HIV to generate hypotheses about potential future treatments. Depression in PWH is characterized by features that differentiate it from depression in people without HIV (PWoH). The first is the predominance of anhedonia - inability to gain enjoyment from activities. The second is a higher prevalence of depression that is resistant to treatment with standard antidepressant drugs in PWH versus PWoH. These clinical observations suggest not only that the underlying pathophysiology of depression is different between the two populations, but that different treatments are needed to successfully treat depression in PWH. Molecular studies of immunometabolism, defined as reciprocal interactions between immunity and metabolism that are dysregulated and linked to depression in PWH, support these distinctions. Based on our preliminary data and that in the literature, we propose to perform RNA-Seq transcriptomics, relating immunometabolic gene expression to protein and other biomarkers of immunometabolism, and to clinical depression as well as to cognitive processes impacted by depression. Our hypothesis-driven approach will focus on two interacting, co-regulated gene pathways central to depression and immunometabolism, the mammalian target of rapamycin (mTOR) and the NLRP3 inflammasome. We will study 80 newly recruited PWH and 40 age- matched PWoH. Given our early work suggesting that the relationship between immunometabolism and depression is sex-dependent, we aim for a 50/50 breakdown of men and premenopausal women in order to examine sex differences in these relationships. To optimize the spectrum of depressive symptom severity in our sample (e.g., avoid over-representation of individuals with minimal depressive symptoms), we will stratify with a 50/50 breakdown above and below the previously established Beck Depression Inventory-II cut-score for clinically-significant depressive symptoms (≥16). Since clinical studies cannot rigorously establish mechanistic relationships, we will study in parallel the roles of mTOR and NLRP3 inflammasome signaling in depression-like behaviors in a mouse model of HIV infection, EcoHIV, which expresses seven of nine key human HIV proteins. These pathways will be dissected using mTOR and NLRP3 inhibitors. Also, in these animals we will characterize immunometabolic markers in brain tissue, presumably the substrate of depression.