Effects of the Integrated Stress Response in HIV Associated Dementia

综合应激反应对 HIV 相关痴呆的影响

• 批准号: 8115124
• 负责人: Kelly L Jordan-Sciutto
• 金额: $ 39.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115124
• 关键词: AIDS Dementia Complex; Address; Affect; Affinity; Alzheimer' s Disease; Anti-Retroviral Agents; Antioxidants; Astrocytes; Autopsy; Brain; Categories; Cells; Cellular Stress; Chaperone Gene; Chronic; Cognitive; Cystine; Data; Degradation Pathway; Dementia; Drug Delivery Systems; Drug usage; Endoplasmic Reticulum; Excitatory Neurotoxins; Exhibits; Glutamate Transporter; Glutamates; Goals; HIV; Highly Active Antiretroviral Therapy; Homeostasis; In Vitro; Individual; Infiltration; Inflammatory; Inositol; Lead; Link; Mediating; Mediator of activation protein; Microglia; Motor; Neuraxis; Neurodegenerative Disorders; Neuronal Dysfunction; Neuronal Injury; Neurons; Oxidative Stress; Pancreas; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; Prevalence; Reactive Oxygen Species; Role; Signal Pathway; Therapeutic; Therapeutic Agents; Transactivation; Viral; Viral Proteins; Virus Diseases; activating transcription factor; activating transcription factor 1; antiporter; attenuation; biological adaptation to stress; brain tissue; central nervous system injury; design; excitotoxicity; in vivo; injured; macrophage; macrophage product; monocyte; neuron loss; neuronal survival; neuropathology; neuroprotection; neurotoxic; neurotoxicity; novel; oxidative damage; promoter; protein degradation; response; stressor

DESCRIPTION (provided by applicant): Despite the introduction of highly active antiretroviral therapy (HAART), the prevalence of human immunodeficiency virus associated dementia (HAD) has been steadily increasing. Neuronal injury and loss in HAD is initiated by HIV-infected, activated macrophage/microglia via soluble neurotoxic mediators including reactive oxygen species (ROS), excitotoxins, and other metabolites as well as viral proteins. These mediators, which induce oxidative stress, are known to injure neurons directly and alter astrocytic homeostatic functions such as glutamate homeostasis which can lead to excitotoxic neuronal injury. Importantly, several studies in vitro and in vivo have shown that oxidative stress and excitotoxicity are likely critical mechanisms of pathogenesis in HAD. How neurons and astrocytes respond to oxidative stress in HIV infection of the central nervous system (CNS) is largely undefined and underexplored. A major downstream response to oxidative stress is induction of the recently described integrated stress response (ISR) which may be the critical link between oxidative stress and excitotoxicity. Activation of the ISR results in translational attenuation, transactivation of ER chaperone gene promoters, activation of protein degradation pathways and activation of the endogenous antioxidant response. Induction of these responses is regulated by one or more of three distinct signaling pathways: pancreatic endoplasmic reticulum kinase (PERK), IRE1 alpha, and ATF6. Whether one or all of these pathways are induced in neuronal or astrocytic cells during HIV induced CNS injury is not known; however, we have demonstrated that supernatants from HIV infected monocyte derived macrophages (HIV-M/M) induce several components of the ISR including PERK in primary astrocytes in vitro. In addition, we have found that several antiretroviral drugs used in HAART also induce ISR in primary astrocytes. Thus, we hypothesize that that activation of the ISR in astrocytes by HIV M/M and/or HAART exposure is a major determinant of neuronal injury/survival in HAD. Our goal is to determine the role of ISR activation in astrocytes by HIV M/M and HAART therapeutics in mediating neuronal damage in vitro and in vivo in HAD. To do this we will: 1) Determine the mechanism by which ISR activation triggered by HIV-M/M supernatants impacts astrocyte neuroprotective functions and survival, 2) Define the role of HAART drugs in ISR activation in astrocytes, and 3) Define and validate the contribution of chronic activation of the ISR pathways in HAD. By investigating the role of ISR, we expect to uncover a novel mechanism for neuronal dysfunction and loss in HIVE and elucidate the impact of current HAART therapeutics on astrocytic mediated neuronal survival. Patients with HIV associated dementia have increased cellular stress in their brain due to inflammatory infiltration and oxidative stress. These stressors are known activate a protective pathway called the integrated stress response in non-neural cells. This proposal aims to assess the state of activation of the integrated stress response in astrocytes exposed to HIV-infected macrophage products and highly active antiretroviral therapeutic agents and determine the impact of such activation on neuronal survival.

描述（由申请人提供）：尽管引入了高度活跃的抗逆转录病毒疗法（HAART），但人类免疫缺陷病毒相关痴呆（HAT）的患病率一直在稳步增加。神经元损伤和丧失是由HIV感染的，活化的巨噬细胞/小胶质细胞通过可溶性神经毒性介质（包括活性氧（ROS），兴奋毒素和其他代谢产物以及病毒蛋白）引发的。这些诱导氧化应激的介质已知会直接损害神经元并改变星形胶质稳态功能，例如谷氨酸稳态，这可能导致兴奋性神经元损伤。重要的是，几项在体外和体内研究表明，氧化应激和兴奋性毒性可能是发病机理的关键机制。神经元和星形胶质细胞如何应对中枢神经系统（CNS）的HIV感染中的氧化应激，在很大程度上不确定且未得到驱动。对氧化应激的主要下游反应是诱导最近描述的综合应力反应（ISR），这可能是氧化应激与兴奋性毒性之间的关键联系。 ISR的激活导致转化衰减，ER伴侣基因启动子的反式激活，蛋白质降解途径的激活以及内源性抗氧化剂反应的激活。这些反应的诱导由三种不同的信号通路中的一个或多个调节：胰腺内质网激酶（PERK），IRE1 alpha和ATF6。在HIV诱导的中枢神经系统损伤期间，在神经元或星形细胞细胞中诱导的一种或全部途径尚不清楚。但是，我们已经证明，来自HIV感染的单核细胞衍生巨噬细胞（HIV-M/M）的上清液诱导ISR的几个成分，包括在体外原代星形胶质细胞中的PERK。此外，我们发现在HAART中使用的几种抗逆转录病毒药物也诱导了原代星形胶质细胞中的ISR。因此，我们假设HIV M/M和/或HAART暴露在星形胶质细胞中激活ISR是神经元损伤/生存的主要决定因素。我们的目标是通过HIV M/M和HAART疗法在体外和体内介导神经元损伤中确定ISR激活在星形胶质细胞中的作用。为此，我们将：1）确定由HIV-M/M上清液触发的ISR激活的机制影响星形胶质细胞神经保护功能和生存，2）确定HAART药物在星形胶质细胞中ISR激活中的作用，并定义和验证ISR途径的Shromonic Actientication ISR中的ISR途径的贡献。通过研究ISR的作用，我们希望发现蜂巢中神经元功能障碍和丧失的新型机制，并阐明当前HAART疗法对星形胶质细胞介导的神经元存活的影响。艾滋病毒相关痴呆的患者由于炎症浸润和氧化应激而增加了大脑的细胞应激。这些应激源已知激活一种称为非神经细胞中综合应力反应的保护途径。该建议旨在评估暴露于HIV感染的巨噬细胞产物和高度活性抗逆转录病毒治疗剂的星形胶质细胞中综合应力反应的激活状态，并确定这种激活对神经元生存的影响。