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NeuroAIDS调控 在后抗逆转录病毒（ART）时代，人类免疫缺陷病毒（HIV）感染不再是 一种致命的疾病相反，HIV+个体随着慢性感染而衰老。因此 艾滋病毒感染的后果与正常衰老在各种疾病中重叠和协同作用。 器官，尤其是大脑。艾滋病病毒感染在中枢神经系统中引发 中枢神经系统（CNS）衰老的几个标志，如认知和运动障碍和痴呆， 无论CD 4水平如何1。然而，这种加速老化的分子方面 艾滋病毒感染者大脑中的过程知之甚少。在这里，使用非人类灵长类动物模型 的neuroAIDS，SIV感染恒河猴，我们将提供初步证据， 感染触发了以前与人类衰老有关的分子标记。我们 我提议探索病毒导致表观遗传途径中断的假设 调节衰老和寿命，这可能是负责增强分子， 加重与CNS功能衰退相关的炎性表型，最终 以脑炎为代表。在这份提案中，我们将解决一个重要问题，即艾滋病毒如何 促进大脑的快速老化，尽管转录的潜在失调， 并由Sirt-1的水平和功能编排，Sirt-1是一种具有深刻意义的分子 对寿命和衰老模型的影响。我们研究了Sirt-1结合到 在对照组和SIV感染的猕猴的小胶质细胞中， 受Sirt-1调控的基因。将我们的分析范围缩小到启动子内的Sirt-1结合位点， 生成了一个分子列表，这些分子可能在炎症的发展中起关键作用。 大脑中的表型。在本申请中，我们的目的是研究这个网络的作用， 分子深入，整合中枢神经系统功能障碍和年龄，了解分子和 衰老常见的炎症环境深层变化的机制基础 和艾滋病毒感染，并协同加重神经系统综合征，即使在后- 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