Neuroimmune mechanisms of depression in adults with HIV infection

 描述（由申请人提供）：本项目的目标是通过分析血浆和CSF外泌体以及外泌体蛋白货物与炎症和犬尿氨酸代谢的关系，了解HIV感染成人抑郁症的神经免疫机制。HIV感染和其他疾病中的全身炎症与抑郁症风险增加相关，其机制涉及改变的Dahan-kynurenine代谢和其他未知机制。外泌体介导炎症和其他条件下的细胞-细胞通信，但它们在抑郁症中的神经免疫相互作用中的作用尚未确定。初步研究显示，与对照组相比，接受ART的HIV患者的循环外泌体水平增加。此外，我们确定了热休克蛋白，Wnt蛋白和其他蛋白质货物在这些外来体与艾滋病毒状态，改变的Dahan-kynurenine代谢和抑郁症状。鉴于失调的Wnt/GSK 3-β信号传导和炎症反应与抑郁症和其他情绪障碍有关，这些发现表明循环外泌体可能在神经免疫相互作用中发挥作用，通过对Wnt/GSK 3-β和/或TLR介导的信号传导的影响影响抑郁症。为了解决这些问题，我们将使用来自纵向跟踪的充分表征的HIV+队列的临床样本和数据来表征血浆和CSF外泌体及其与抑郁症、炎症标志物和Dahan-kynurenine代谢物的关系。生物信息学、计算建模和细胞培养模型将用于构建和测试预测抑郁状态和相关途径的模型。这种方法可以定义循环外泌体货物和HIV感染中抑郁症的神经免疫机制之间的新关系，可能表明基于外泌体生物学的新治疗靶点。

 DESCRIPTION (provided by applicant): The goal of this project is to understand neuroimmune mechanisms of depression in adults with HIV infection through analysis of plasma and CSF exosomes and the relationship of exosome protein cargo to inflammation and tryptophan-kynurenine metabolism. Systemic inflammation in HIV infection and other conditions is associated with increased risk of depression through mechanisms involving altered tryptophan-kynurenine metabolism and other unknown mechanisms. Exosomes mediate cell-cell communication during inflammation and other conditions, but their role in neuroimmune interactions involved in depression have not been defined. Preliminary studies showed increased levels of circulating exosomes in HIV patients on ART compared to controls. Moreover, we identified heat shock proteins, Wnt proteins, and other protein cargo in these exosomes that correlate with HIV status, altered tryptophan-kynurenine metabolism, and depressive symptoms. Given that dysregulated Wnt/GSK3-β signaling and inflammatory responses have been linked to depression and other mood disorders, these findings suggest that circulating exosomes may play a role in neuroimmune interactions that impact depression through effects on Wnt/GSK3-β and/or TLR-mediated signaling. To address these questions, we will use clinical samples and data from well characterized HIV+ cohorts followed longitudinally to characterize plasma and CSF exosomes and their relationship to depression, inflammation markers, and tryptophan-kynurenine metabolites. Bioinformatics, computational modeling, and cell culture models will be used to build and test models that predict depression status and relevant pathways. This approach may define novel relationships between circulating exosome cargo and neuroimmune mechanisms of depression in HIV infection, potentially suggesting new therapeutic targets based on the biology of exosomes.