Neuroimmune mechanisms of depression in adults with HIV infection

 描述(申请人提供)：本项目的目标是通过分析血浆和脑脊液外切体以及外切体蛋白与炎症和色氨酸-犬尿氨酸代谢的关系，了解成年HIV感染患者抑郁的神经免疫机制。艾滋病毒感染和其他情况下的全身炎症通过涉及色氨酸-犬尿氨酸代谢改变和其他未知机制的机制，与抑郁风险增加有关。Exosome在炎症和其他条件下调节细胞间的通讯，但它们在抑郁症涉及的神经免疫相互作用中的作用尚未确定。初步研究表明，与对照组相比，接受抗逆转录病毒治疗的艾滋病毒患者的循环外切体水平增加。此外，我们在这些外体中鉴定了热休克蛋白、Wnt蛋白和其他与HIV状态、色氨酸-犬尿氨酸代谢改变和抑郁症状相关的蛋白。鉴于Wnt/Gsk3-β信号和炎症反应的失调与抑郁和其他情绪障碍有关，这些发现提示，循环外切体可能通过影响Wnt/Gsk3-β和/或TLR介导的信号在神经免疫相互作用中发挥作用，从而影响抑郁。为了解决这些问题，我们将使用纵向追踪的具有良好特征的HIV+队列的临床样本和数据来表征血浆和脑脊液外切体及其与抑郁症、炎症标记物和色氨酸-犬尿氨酸代谢物的关系。生物信息学、计算建模和细胞培养模型将被用于建立和测试预测抑郁状态和相关途径的模型。这一方法可能定义循环外切体货物与HIV感染中抑郁的神经免疫机制之间的新关系，潜在地提出基于外切体生物学的新的治疗靶点。

 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.