Sirt-1-mediated regulation of NeuroAIDS

Sirt-1 介导的 NeuroAIDS 调节

基本信息

批准号：
9267292
负责人：
Maria Cecilia Garibaldi Marcondes
金额：
$ 0.23万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2017-09-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9267292
关键词：
19 year old Address Age Aging Aging-Related Process Anti-Retroviral Agents Binding Binding Sites Biological Markers Brain Candidate Disease Gene Cells Chromatin Chronic 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 Phenotype Regulation Role SIV Sampling Synapses Synaptophysin Syndrome Transcriptional Regulation Viral reservoir Virus aging brain brain tissue cell type cohort frontal lobe genome-wide inflammatory marker inflammatory milieu mind control molecular marker motor disorder neuroAIDS nonhuman primate promoter senescence

项目摘要

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 调节在后抗逆转录病毒（ART）时代，人类免疫缺陷病毒（HIV）感染不再是致命的情况。相反，艾滋病病毒感染者会随着慢性感染而衰老。因此， HIV 感染的后果与各种正常衰老现象重叠并协同作用器官，特别是大脑。人们普遍认为艾滋病毒感染会在中枢神经系统中引发系统（CNS）衰老的几个标志，例如认知和运动障碍以及痴呆，无论 CD4 水平如何1。然而，分子方面强调了这种加速衰老人们对感染艾滋病毒的大脑中的这一过程知之甚少。这里，使用非人类灵长类动物模型恒河猴的神经艾滋病、SIV感染，我们将提供初步证据表明感染会触发先前与人类衰老相关的分子标记。我们提议探索病毒导致表观遗传途径破坏的假设调节衰老和寿命，负责增强分子最终加剧与中枢神经系统功能衰退相关的炎症表型以脑炎为代表。在本提案中，我们将解决一个重要问题，即艾滋病毒如何通过潜在的转录失调促进大脑快速衰老并由 Sirt-1 的水平和功能精心策划，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 结合的动力学研究人员对对照和感染 SIV 的猕猴的小胶质细胞中的染色质进行了研究，并确定了一个网络 Sirt-1 调控的基因。将我们的分析范围缩小到启动子内 Sirt-1 结合位点，我们生成了可能在炎症发展中起关键作用的分子列表大脑中的表型。在此应用程序中，我们旨在研究该网络的作用深入分子，整合中枢神经系统功能障碍和年龄，了解分子和衰老过程中常见的炎症环境深层变化的机制基础和艾滋病毒感染，并且协同作用加重神经系统综合症，即使在感染后艺术时代。