Sirt-1-mediated regulation of NeuroAIDS

Sirt-1 介导的 NeuroAIDS 调节

• 批准号: 9547742
• 负责人: Maria Cecilia Garibaldi Marcondes
• 金额: $ 23.78万
• 依托单位: SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9547742
• 关键词: 19 year old; Address; Age; Aging; Anti-Retroviral Agents; Binding; Binding Sites; Biological Markers; Brain; Candidate Disease Gene; Cells; Chromatin; Cognition Disorders; Consequences of HIV; Dementia; Development; Encephalitis; Environment; Epigenetic Process; Exhibits; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Gliosis; HIV; HIV Infections; Health; Histones; Human; Immunohistochemistry; Impaired cognition; In Situ Hybridization; Individual; Infection; Inflammation; Inflammatory; Intervention Studies; Liquid substance; Longevity; Macaca; Macaca mulatta; Maps; Measures; Mediating; Microglia; Modeling; Molecular; Monkeys; Neuraxis; Neuroglia; Neurologic; Organ; Pathogenesis; Pathology; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Process; Regulation; Role; SIV; Sampling; Synapses; Synaptophysin; Syndrome; Viral reservoir; Virus; Virus Diseases; aging brain; brain tissue; cell type; chronic infection; cohort; frontal lobe; genome-wide; inflammatory marker; inflammatory milieu; mind control; molecular marker; motor disorder; neuroAIDS; nonhuman primate; promoter; senescence

Sirt-1-mediated regulation of NeuroAIDS In the post anti-retrovirals (ART) era, human immunodeficiency virus (HIV) infection is no longer a deadly condition. Rather, HIV+ individuals age with the chronic infection. Therefore, the consequences of HIV infection overlap and synergize with normal senescence in various organs, especially the brain. It is accepted that HIV infection triggers in the Central Nervous System (CNS) several hallmarks of aging, such as cognitive and motor disorders and dementia, regardless of CD4 levels1. However, the molecular aspects underlining this accelerated aging process in HIV-infected brains are poorly understood. Here, using the non-human primate model of neuroAIDS, SIV infection of rhesus macaques, we will provide preliminary evidence that the infection triggers molecular markers that were previously associated to aging in humans. We propose to explore the hypothesis that the virus causes a disruption of an epigenetic pathway that regulates aging and lifespan, which can be responsible for enhancing molecules that aggravate the inflammatory phenotype associated with CNS functional decay, ultimately represented by encephalitis. In this proposal we will address an important problem of how HIV promotes a rapid aging of the brain though a potential dysregulation of transcription, centered and orchestrated by the levels and function of Sirt-1, which is a molecule with profound implications to lifespan and in aging models. We studied the dynamics of Sirt-1 binding to chromatin in microglia from control and SIV-infected macaques, and identified a network of genes regulated by Sirt-1. Narrowing our analysis to in-promoter Sirt-1 binding sites, we generated a list of molecules that may have a critical role in the development of an inflammatory phenotype in the brain. In this application, we aim at examining the role of this network of molecules in depth, integrating CNS dysfunction and age, to understand the molecular and mechanistic basis for deep changes in the inflammatory environment that are common to aging and to HIV infection, and that synergize to aggravate neurological syndromes, even in the post- ART era.

SIRT-1介导的神经辅助调节 在抗逆转录病毒后（ART）时代，人类免疫缺陷病毒（HIV）不再是 致命的状况。相反，艾滋病毒+患者患有慢性感染。因此， 艾滋病毒感染的后果重叠并与正常衰老协同作用。 器官，尤其是大脑。人们认为，艾滋病毒感染引发了中枢神经 系统（CNS）衰老的几个标志，例如认知和运动障碍和痴呆， 不论CD4级别1。但是，强调这种加速衰老的分子方面 感染HIV的大脑过程知之甚少。在这里，使用非人类灵长类动物模型 关于神经辅助，恒河猕猴的SIV感染，我们将提供初步证据表明 感染会触发与人类衰老有关的分子标记。我们 提议探讨该病毒导致表观遗传途径中断的假设 调节衰老和寿命，这可能是为了增强分子 加重与CNS功能衰减相关的炎症表型，最终 以脑炎为代表。在此提案中，我们将解决一个重要的问题 尽管转录的潜在失调，促进大脑的快速衰老，以中心为中心 并由SIRT-1的水平和功能策划，这是一个具有深刻的分子 对寿命和衰老模型的影响。我们研究了SIRT-1结合的动力学 来自对照和SIV感染猕猴的小胶质细胞中的染色质，并确定了一个网络 由SIRT-1调节的基因。将我们的分析范围缩小到启动中的SIRT-1绑定站点，我们 产生了可能在炎症发展中具有关键作用的分子列表 大脑中的表型。在此应用程序中，我们旨在检查该网络的作用 深度分子，整合CNS功能障碍和年龄，以了解分子和 衰老常见的炎症环境中深层变化的机理基础 并引起艾滋病毒感染，即使在后期 艺术时代。

项目成果

Age-associated changes in microglia activation and Sirtuin-1- chromatin binding patterns.

• DOI: 10.18632/aging.204329
• 发表时间: 2022-10-10
• 期刊: AGING-US
• 影响因子: 5.2
• 作者: Basova, Liana, V;Bortell, Nikki;Conti, Bruno;Fox, Howard S.;Milner, Richard;Marcondes, Maria Cecilia Garibaldi
• 通讯作者: Marcondes, Maria Cecilia Garibaldi