Iron Dysregulation and Neuropsychiatric Complications of HIV Across the Lifespan: Impact of Biologic Factors, Antiretroviral Therapy and Genetics

HIV整个生命周期中的铁失调和神经精神并发症：生物因素、抗逆转录病毒治疗和遗传学的影响

• 批准号: 10356168
• 负责人: ASHA R KALLIANPUR
• 金额: $ 54.36万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356168
• 关键词: Address; Age; Aging; Animals; Anti-Retroviral Agents; Biological Factors; Biological Markers; Brain; Cerebrospinal Fluid; Chemicals; Clinical; Cognition; Cognitive; Cohort Studies; Data Set; Deltastab; Depressed mood; Development; Diagnostic; Disease; Disease Management; Dopamine; Elderly; Energy Metabolism; Epidemiology; Equilibrium; Frequencies; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genomics; HIV; HIV Infections; HIV Seropositivity; High Prevalence; Homeostasis; Homovanillic Acid; Human; Immune; Impaired cognition; In Vitro; Individual; Inflammation; Integrase; Intervention; Iron; Joints; Kynurenine; Link; Longevity; Longitudinal Studies; Major Depressive Disorder; Measures; Mediating; Mental Depression; Metabolic; Metabolism; Microglia; Mitochondria; Modeling; Moods; Neurocognitive Deficit; Neurons; Neurotransmitters; Participant; Pathway Analysis; Pathway interactions; Persons; Pharmaceutical Preparations; Predisposition; Production; Proteins; Quality of life; Quantitative Trait Loci; Recording of previous events; Regulator Genes; Research; Risk; Role; Serotonin; Serum; Sex Differences; Substance abuse problem; Testing; Woman; Work; age effect; antiretroviral therapy; bioinformatics network; cohort; comorbidity; experience; follow-up; gene network; genome wide association study; genome-wide; genomic data; indexing; inhibitor; iron metabolism; knock-down; medication compliance; medication nonadherence; men; monoamine; mortality; myelination; neural circuit; neuroAIDS; neurobiological mechanism; neurogenesis; neuroinflammation; neuropsychiatric disorder; neuropsychiatry; neurotoxic; neurotransmitter metabolism; novel; older women; precision medicine; prospective; sex; treatment strategy

ABSTRACT People with HIV experience a much higher prevalence of depression and neurocognitive impairment (NCI) than the general population, and these disorders frequently co-occur, reducing medication adherence and quality of life and increasing mortality at least two-fold. Studies with large numbers of women as well as men are urgently needed to elucidate the neurobiologic mechanisms underlying these disorders as well as recently identified sex differences in vulnerability. Microglia-mediated neuro-inflammation and alterations in the Kynurenine Pathway (KP), which is essential for maintaining balanced mono-amine neurotransmitter (e.g., dopamine and serotonin) synthesis in the brain, are implicated in both disorders. Iron, dysregulated by HIV and combination antiretroviral therapy (cART), is intimately involved in microglial activation, the KP, and neurotransmitter metabolism. Our preliminary studies in a single neuro-HIV cohort and in HIV(-) persons indicate a significant role for dysregulated iron metabolism and iron-related gene networks in depression and NCI, as well as sex-specific effects. The proposed study leverages existing clinical, iron-biomarker, and genome-wide datasets from three large prospective HIV cohort studies to powerfully and comprehensively interrogate the role of iron in depression and NCI in both sexes. A combination of serum and cerebrospinal-fluid (CSF) biomarker, iron-centered genome-wide associations, and network bioinformatics approaches will be employed. Central hypotheses of this proposal are that iron dysregulation, and iron-related genes/networks, are major contributors to depression and NCI in PWH, with variability in overall risk explained in part by age, sex, HIV, and cART effects on iron. The Specific Aims are: 1) Determine the role of altered iron homeostasis in depression and NCI in PWH across the age spectrum and the proportion of susceptibility that is attributable to the effects of biologic factors, HIV, and cART on iron; 2) Identify novel iron-dependent pathways, iron-metabolic genes, and iron-quantitative trait loci associated with depression and NCI in women and men with HIV, and determine the extent to which these genetic effects are mediated via iron; 3) Explore the functional impact of network-prioritized iron-related gene knockdown on production of KP metabolites, using an in vitro HIV(+/-) human microglia model. In addition, Aim 1 will associate iron indices in a subset of individuals to CSF mono-amine metabolites. We expect these studies to advance understanding of mechanisms leading to depression and NCI in people with HIV, suggesting novel precision- medicine approaches to disease management and potentially impactful, iron- or KP-modulating interventions.

抽象的 艾滋病毒患者的抑郁症和神经认知障碍的患病率要高得多（NCI） 比普通人群，这些疾病经常同时发生，降低了药物的依从性和质量 生命和死亡率提高至少两倍。与男性和男性大量的研究 需要阐明这些疾病的基础神经生物学机制以及最近确定的性别 脆弱性差异。小胶质细胞介导的神经炎症和Kynurenine途径的改变 （KP），这对于维持平衡的单胺神经递质（例如多巴胺和5-羟色胺）至关重要 大脑中的合成均与两种疾病有关。铁，艾滋病毒和抗逆转录病毒组合失调 治疗（CART）与小胶质细胞激活，KP和神经递质代谢密切相关。我们的 在单个神经HIV队列和HIV（ - ）中的初步研究表明，失调的重要作用 抑郁症和NCI中的铁代谢和与铁相关的基因网络以及性别特异性作用。这 拟议的研究利用了三个大型大型的现有临床，铁生物标志物和全基因组数据集 前瞻性艾滋病毒队列研究有效，全面地询问铁在抑郁症和 两性中的NCI。血清和脑脊液 - 流体（CSF）生物标志物，以铁为中心的基因组的组合 将采用关联和网络生物信息学方法。该提议的中心假设是 铁失调和与铁相关的基因/网络是PWH中抑郁症和NCI的主要因素， 由于年龄，性别，艾滋病毒和手推车对铁的影响，总体风险的变化部分差异。具体目的是： 1）确定铁稳态改变在抑郁症和NCI中的作用，在整个年龄范围内PWH中 归因于生物因素，艾滋病毒和推车对铁的影响的易感性的比例； 2） 鉴定与与 艾滋病毒男性和男性的抑郁症和NCI，并确定这些遗传影响的程度 通过铁介导； 3）探索与网络优先铁相关的基因敲低的功能影响 使用体外HIV（+/-）人类小胶质细胞模型的KP代谢产物产生。此外，AIM 1将关联 在CSF单胺代谢物的一个个体中的铁指数。我们希望这些研究能够进步 了解导致艾滋病毒患者抑郁和NCI的机制，这表明了新颖的精度 - 疾病管理和潜在影响，铁或KP调节干预措施的医学方法。