Scrutinizing neuro-immune regulatory mechanisms underlying depressive symptomatology in young adults with HIV

仔细检查年轻艾滋病毒感染者抑郁症状背后的神经免疫调节机制

基本信息

批准号：
10370250
负责人：
Suzi Hong
金额：
$ 19.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370250
关键词：
Adherence Adrenal Glands Adrenergic Receptor Affect Affective Agonist Anhedonia Anisotropy Anterior Behavioral Biological Blood Brain Brain region CD4 Positive T Lymphocytes Caregivers Cell Count Cell model Cell physiology Choline Clinical Cognitive Coupled Data Demographic Factors Diffusion Magnetic Resonance Imaging Etiology Exploratory/Developmental Grant Functional disorder Future Glucocorticoid Receptor Glucocorticoids HIV HIV Infections Health Healthcare High Prevalence Immune Individual Inflammation Inflammatory Inositol Investigation Knowledge Lead Magnetic Resonance Spectroscopy Major Depressive Disorder Measures Mediating Mediator of activation protein Mental Depression Modality Modeling Mood Disorders Moods Morbidity - disease rate Neurobiology Neuroimmune Neurons Neurosecretory Systems Participant Pathway interactions Plasma Population Quality of life Regulation Reporting Research Role Structure Symptoms Time Viral Viral Load result Youth aged brain pathway clinically relevant depressive symptoms imaging biomarker immune function inflammatory marker insight marijuana use monocyte mortality multimodality neuroimaging neuroimaging marker neuroinflammation peripheral blood psychologic psychosocial receptor response sociodemographics symptomatology targeted treatment therapeutic target treatment adherence white matter young adult

项目摘要

Project Summary/Abstract Mood disorders are prevalent among individuals living with HIV for which multi-dimensional, contributing factors exist. Especially, 20-50% of youth living with HIV (YWH) report depression or elevated depressive symptoms of clinical relevance. Depression or elevated depressive symptoms in YWH result in HIV include poor adherence to HIV treatment, poor viral suppression, increased morbidity and mortality as well as decreased quality of life. In spite of growing data showing the association between blood inflammatory markers and levels of depressive mood or clinical depression in HIV- and HIV+ individuals, inconsistent findings across the studies in the inflammatory marker-depression associations pose challenges in understanding mechanisms and lead to a paucity of targeted therapeutics. Given the profound modulatory effects of multiple branches of the neuroendocrine system on immune/inflammatory activities, we propose to conduct simultaneous investigations of potentially concurrent but disparate neuro-immune pathways (“NIP”) of inflammation dysregulation (IR) in predicting depressive symptoms in 45 YWH and 45 Control youth (aged 18-25 yrs), by leveraging an ongoing R01 study of brain function and cannabis use in YWH (DA047906). We will employ an ex vivo cellular model of peripheral blood monocytes by which effects of various receptor agonists in cellular IR will be assessed [1) sympatho-adrenal (SA)/adrenergic receptor (AR); 2) glucocorticoid (GC)/GC receptor (GR), and 3) dopaminergic (DA)/DR pathways] in predicting depressive symptoms (Aim 1). The neuroimaging markers of neuroinflammation from R01 [1) diffusion tensor imaging measures (e.g., fractional anisotropy), 2) structural alterations (i.e., white matter abnormality), and 3) metabolites through MR Spectroscopy (i.e., higher choline and myo-inositol, indicating diminished neuronal integrity and increased inflammation)] will be examined as a mediator (Aim 2). We will also explore differing depressive symptom domains [1) cognitive, 2) affective, and 3) somatic domains as well as 4) apathy and 5) anhedonia], as initial evidence shows symptoms specific to HIV infection such as somatic symptoms and apathy which may provide insight into delineating NIP- brain regions-symptoms network (Aim 3). Many types of the data collected in the R01 study will be shared with this R21 such as sociodemographic; clinical; psychological and behavioral; and neuroimaging data, maximizing the feasibility of this R21. Our simultaneous investigation of three NIP pathways with careful analytical plans in predicting depressive symptoms will provide an opportunity to gain mechanistic knowledge beyond plasma inflammatory marker-depression associations and to inform targeted therapeutic modalities.

项目概要/摘要情绪障碍在艾滋病毒感染者中普遍存在，其原因是多方面的、有影响的尤其是，20-50% 的艾滋病毒感染者 (YWH) 患有抑郁症或抑郁症加重。 YWH 导致 HIV 的临床相关症状包括：对艾滋病毒治疗的依从性差、病毒抑制效果差、发病率和死亡率增加以及尽管越来越多的数据显示血液炎症标志物之间的关联。 HIV 感染者和 HIV+ 个体的抑郁情绪或临床抑郁水平，不同研究结果不一致炎症标志物与抑郁症关联的研究对理解机制提出了挑战并导致缺乏靶向治疗。神经内分泌系统对免疫/炎症活动的影响，我们建议同时进行对炎症的潜在并发但不同的神经免疫途径（“NIP”）的研究调节失调（IR）在预测 45 YWH 和 45 对照青年（18-25 岁）的抑郁症状中，通过利用正在进行的关于 YWH 大脑功能和大麻使用的 R01 研究 (DA047906)，我们将采用一个外周血单核细胞的离体细胞模型，通过该模型各种受体激动剂对细胞IR的影响将进行评估 [1) 交感肾上腺 (SA)/肾上腺素能受体 (AR)；2) 糖皮质激素 (GC)/GC 受体 (GR) 和 3) 多巴胺能 (DA)/DR 通路] 预测抑郁症状（目标 1）。 R01 的神经炎症标志物 [1) 扩散张量成像测量（例如分数各向异性），2) 结构改变（即白质异常），以及 3）通过 MR 波谱检查的代谢物（即更高胆碱和肌醇，表明神经完整性减弱和炎症增加）]将我们还将探索不同的抑郁症状领域 [1) 认知，2)。情感，3) 躯体领域以及 4) 冷漠和 5) 快感缺失]，正如初步证据显示的症状 HIV 感染特有的症状，如躯体症状和冷漠，这可能有助于深入描述 NIP- 大脑区域-症状网络（目标 3）将与 R01 研究中收集的许多类型的数据共享。 R21，例如社会人口统计学、心理和行为以及神经影像数据；我们通过仔细的分析计划同时研究了三个 NIP 途径的可行性。预测抑郁症状将为获得血浆以外的机制知识提供机会炎症标志物与抑郁症的关联并为有针对性的治疗方式提供信息。