Threshold of Cognitive Impairment after HIV Infection: Effect of Morphine

HIV 感染后认知障碍的阈值：吗啡的作用

基本信息

批准号：
8712082
负责人：
DAVID J VOLSKY
金额：
$ 80.6万
依托单位：
ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2014-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8712082
关键词：
Acquired Immunodeficiency Syndrome Alcohol or Other Drugs use Animal Model Animals Anti-Retroviral Agents Antiviral Agents Archives Benign Biochemical Bioinformatics Biology Brain Brain Diseases Brain Injuries Brain Pathology Cells Chronic Clinical Cognition Cognition Disorders Data Dementia Diagnosis Disease Disease Marker Dose Epigenetic Process Frequencies Functional disorder Gene Silencing Genes Genetic Transcription Geographic Locations Goals HIV HIV Infections Heroin Histones Human Immune Immune response Immunity Immunocompetent Immunology Impaired cognition Impairment Individual Infection Injury Intervention Knock-out Knockout Mice Learning Link Lysine Mediating Mediator of activation protein Memory Methylation Modeling Molecular Morphine Mus Mutant Strains Mice Natural History Neurocognitive Neuropathogenesis Opiate Addiction Opiates Opioid Receptor Pathogenesis Patients Performance Pharmacologic Substance Physiological Placebos Potassium Hydroxide Process Recovery Refractory Relative (related person)Research Role Route Site Specificity Substance abuse problem Symptoms Synapses Synaptic plasticity System Systemic infection Systems Biology Testing Time Tissue Banking Tissue Banks Tissues Variant Viral Virus antiretroviral therapy base behavior test brain tissue calmodulin-dependent protein kinase II chromatin immunoprecipitation chromatin remodeling design efficacy testing histone modification human disease immune function implantation inhibitor/antagonist innovation knowledge base learned behavior neuropathology novel pre-clinical prevent programs promoter public health relevance research study success synaptic function transmission process treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Presently antiretroviral therapies can preserve or restore immune function in HIV-infected people, but roughly 50% of them succumb to mild sub-dementia forms of HAND that are largely refractory to treatment. We propose innovative research to test the new hypothesis that the pathogenic processes responsible for HAND ensue early after virus transmission, they persist despite later antiviral or immune control of virus, an they may be exacerbated by opiate use. The testable translational implication of this hypothesis is that therapies targeting key determinants of the early neuropathogenesis may prevent HAND. The hypothesis will be tested in an established system of HIV infection and early cognitive impairment in immunocompetent mice inoculated with mouse-tropic HIV, EcoHIV. The natural history of cognitive disease in these mice closely models mild HAND in HIV-infected humans. HIV enters the mouse brain within 5 days of systemic infection with cognitive impairments developing 4-5 weeks later and persisting despite adaptive antiviral immunity and virus suppression. Brain pathology was normal but cognitive dysfunction correlated with suppression of synaptic plasticity genes including CaMKII and SYN2; both genes also had gene-silencing epigenetic modifications of histone 3 on their promoters as determined by chromatin immunoprecipitation, suggesting stable disruption of some synaptic functions in HAND. Chronic morphine exposure and HIV synergized in causing cognitive impairment in mice. We postulate that the brain injury inflicted soon after infection of mice, before establishment of adaptive immune responses, is largely irreversible and initiates a neuropathogenic program leading to cognitive impairment. The overall goals of this application are to test this proposition, explore selected mechanisms involved, and apply the findings to identify therapies to prevent HAND. The Aims are: 1) To define virological and synaptic determinants of subclinical HAND and its progression to clinical disease; 2) To determine morphine effects in subclinical and clinical HAND; 3) To test a novel mechanism of pan- dysregulation of synaptic plasticity genes in murine HAND by chromatin remodeling and the potential role of Tat; 4) To explore interventions disrupting preclinical HAND to prevent progression to clinical disease. We believe that use of cognitive impairment as a relevant disease readout, combined with versatility of mouse experimentation, will facilitate identification of key physiological and molecular processes involved in HAND. Studies will be conducted exclusively in mice, both conventional and specific knock-out strains, principally through systemic infection with EcoHIV, with/without chronic morphine treatment through implantation of timed- release pellets. Selected disease markers identified in mice will be confirmed in archival brain tissues of MND patients stratified by opiate addiction. Timed interventions will include inhibitors of chromatin remodeling.

描述（由申请人提供）：目前的抗逆转录病毒疗法可以保留或恢复感染HIV感染的人的免疫功能，但大约有50％的人屈服于轻度亚dentia形式的手，在很大程度上是对治疗的难治性的。我们提出了创新的研究，以检验新的假设，即病毒传播后尽早导致手动的致病过程，尽管后来对病毒的抗病毒或免疫控制，它们仍然会因鸦片使用而加剧。该假设的可检验的翻译意义是，针对早期神经病发生的关键决定因素的治疗可能会阻止手。该假设将在已建立的HIV感染系统和早期认知障碍系统中进行检验。这些小鼠的认知疾病的自然历史与感染了艾滋病毒感染的人的轻度手密切模型。 HIV在全身感染后的5天内进入小鼠大脑，并在4-5周后出现认知障碍，尽管自适应抗病毒药和抑制病毒，但仍持续存在。脑病理是正常的，但认知功能障碍与包括Camkii和Syn2在内的突触可塑性基因的抑制相关。通过染色质免疫沉淀确定，这两个基因还对其启动子上组蛋白3的基因表观遗传修饰进行了改性，这表明手头上某些突触功能的破坏稳定。慢性吗啡暴露和HIV在导致小鼠的认知障碍方面协同作用。我们假设，在建立适应性免疫反应之前，小鼠感染后不久造成的脑损伤在很大程度上是不可逆的，并启动了神经病发明程序，导致认知障碍。该应用程序的总体目标是测试该主张，探索所涉及的选定机制，并应用发现以识别疗法以防止手。目的是：1）定义亚临床手的病毒学和突触决定因素及其发展为临床疾病； 2）确定亚临床和临床手中的吗啡效应； 3）通过染色质重塑和TAT的潜在作用来测试鼠手中突触可塑性基因失调的新型机制； 4）探索干预措施破坏了临床前手，以防止临床疾病进展。我们认为，将认知障碍用作相关的疾病读数，再加上小鼠实验的多功能性，将有助于鉴定与手头有关的关键生理和分子过程。研究将仅在传统和特定的敲除菌株中，主要是通过全身感染EcoHIV进行的，并通过植入定时释放颗粒而进行慢性吗啡治疗。在小鼠中鉴定出的选定疾病标志物将在通过阿片类药物分层的MND患者的档案脑组织中确认瘾。定时干预将包括染色质重塑的抑制剂。