Neurodegeneration in Aged SIV-Infected Primates

老年 SIV 感染灵长类动物的神经退行性疾病

基本信息

批准号：
9031156
负责人：
STEPHANIE J BISSEL
金额：
$ 57.77万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9031156
关键词：
20 year old AIDS Dementia Complex Acquired Immunodeficiency Syndrome Age Aging Aging-Related Process Amyloid beta-Protein Animal Disease Models Animals Anti-Retroviral Agents Astrocytosis Autopsy Behavioral Blood Brain CD4 Lymphocyte Count Centers for Disease Control and Prevention (U.S.)Chronic Chronology Cognitive Complex Consequences of HIV Coupled Deposition Developed Countries Disease Disease Marker Elderly Electrolytes Encephalitis Exposure to Extracellular Matrix Freezing Future Grant HIV HIV Infections HIV antiretroviral HIV-associated neurocognitive disorder Health Highly Active Antiretroviral Therapy Human Immunosuppression Incidence Individual Infection Intervention Investigation Knowledge Link Macaca Macaca mulatta Maps Modeling Monitor Monkeys Motor Nerve Degeneration Nervous System Trauma Nervous system structure Neuraxis Neurocognitive Neurodegenerative Disorders Neurofibrillary Tangles Neurologic Neurologic Dysfunctions Neuropathogenesis Pathogenesis Pathway interactions Patients Performance Pharmaceutical Preparations Plasma Prevalence Primates Proteins RNA Risk Role SIV SIV encephalitis Sensory Short-Term Memory Stress Synapses Systemic disease Techniques Temperature Testing Therapeutic Time Training Viral Viral Load result Virus Diseases age group age related age related neurodegeneration aged aging brain antiretroviral therapy axon injury behavior measurement classical conditioning experience human disease immune activation immunosuppressed middle age motor disorder nervous system disorder neuroinflammation neuron loss neuropathology neuropsychiatry nonhuman primate sustained attention tau Proteins tau mutation tau phosphorylation therapy design white matter damage

项目摘要

DESCRIPTION (provided by applicant): This is a new RO1 entitled "Neurodegeneration in aged SIV-infected primates" that is a direct extension of our previously investigations in the pathogenesis of SIV encephalitis and neurodegeneration in aged non-human primates. Use of combined active antiretrovirals (CART) in developed countries has led to a near disappearance of severe encephalitis. Unfortunately chronic HIV infection continues to exact a toll on the nervous system with increased prevalence of a spectrum of neurocognitive and motor dysfunctions termed HIV-associated neurocognitive disorders (HAND). CART has also permitted people to survive longer with HIV infection and the CDC projects that by 2015 over half of HIV infected individuals in the US will be over the age of 50. Coupled with the aging process, the extended exposure to both HIV and antiretroviral drugs appears to increase their risk of neurologic and neuropsychiatric complications. In this application we propose to use a well-established non-human primate (NHP) model of chronic lentiviral infection, SIV infection of Macaca mulatta (Rhesus Macaque RM), to model HAND in aged macaques (>20 years old), map the neurological signs to behavioral abnormalities and begin to elucidate the neurological and immunological pathogenesis of this debilitating disease. While no animal disease model is perfect, numerous similarities between simian and human nervous systems, between SIV and HIV infection and the capacity to manipulate and monitor central nervous system (CNS) damage, make the macaque model optimal for these studies. Using 5 groups of SIV infected and control RMs, we will assess the presence of neurocognitive abnormalities and the role of viral suppression in exacerbating age related neurodegeneration. Findings from this grant will have immediate implications on the treatment of aged HIV infected humans. Building upon our previous decade of experience with SIV infection of macaques as a model of chronic HIV infection and our recent studies of neuroinflammation in aged NHPs (Kofler et al 2011 (41) see appendix), we will test our overarching hypothesis that: chronic systemic CART with or without chronic lentiviral infection exacerbates age related damage to the nervous system principally through CNS stress and associated innate immune activation. We will assess whether aggressive suppression of systemic lentiviral infection with CART exacerbates age related cognitive abnormalities and beta amyloid related neuropathology (e.g. plaques, tangles, abnormal tau phosphorylation or beta amyloid oligomeres). Alternatively, HAND may persist even in the presence of viral suppression or as a result of CART alone. In our second specific aim we will use state of the art quantitative neuropathological analysis to elucidate the pathological substrate of HAND. Knowledge of the pathogenesis of neurological dysfunction in the simian model will help define pathways for intervention to mitigate the human disease.

描述（由申请人提供）：这是一种新的RO1，标题为“衰老的SIV感染灵长类动物的神经变性”，是我们先前研究的SIV脑炎发病机理和神经变性的直接扩展。发达国家使用积极的抗逆转录病毒（CART）已导致严重脑炎几乎消失。不幸的是，慢性艾滋病毒感染继续使神经系统造成损失，而神经认知和运动功能障碍的患病率增加，称为HIV相关的神经认知疾病（Hand）。推车还允许人们在艾滋病毒感染中生存更长的时间，而疾病预防控制中心（CDC）预测，到2015年，美国一半的艾滋病毒感染者将超过50岁。再加上衰老过程，艾滋病毒和抗逆转录病毒药物的扩展暴露似乎增加了他们的神经学和神经心理心理并发症的风险。在此应用中，我们建议使用慢性慢病毒感染的良好非人类灵长类动物（NHP）模型，Macaca Mulatta的SIV感染（Rhesus Macaque RM）模拟老年猕猴（> 20岁）（> 20岁），将神经学迹象映射到神经学的疾病和开始的疾病中，并逐渐启动了这种疾病的病态，并逐渐启动了这种疾病。尽管没有动物疾病模型是完美的，但猿猴和人类神经系统，SIV和HIV感染之间的许多相似之处以及操纵和监测中枢神经系统（CNS）损害的能力，使猕猴模型最适合这些研究。使用5组感染和控制RMS的SIV组，我们将评估神经认知异常的存在以及病毒抑制在加剧年龄相关的神经变性中的作用。这笔赠款的发现将对对艾滋病毒感染的人类的治疗产生直接影响。基于我们前十年的SIV感染猕猴作为慢性HIV感染的模型以及我们最近对NHP的神经炎症的模型的基础（Kofler等人（41），请参见附录），我们将测试我们的总体假设，该假设是：与持续性的慢性疫苗症状相关的持续性造成慢性疾病的持续性损害，不管是慢性疾病的持续性疾病，均与慢性疾病相关的疾病，持续性疾病的持续性疾病，持续性疾病的持续性疾病，持续性疾病的持续性疾病症状症状与持续性的持续性造成紧张的疾病，持续性疾病的持续性疾病症状症状症状相关。激活。我们将评估对全身性慢病毒感染的积极抑制是否加剧了与年龄相关的认知异常和β-淀粉样蛋白相关的神经病理学（例如，斑块，缠结，缠结，tanmal tau磷酸化异常或β淀粉样蛋白寡聚物）。或者，即使在存在病毒抑制或单独的卡车后，手也可能持续。在我们的第二个特定目标中，我们将使用最先进的定量神经病理学分析来阐明手的病理底物。妈妈模型中神经功能障碍的发病机理的了解将有助于定义干预途径以减轻人类疾病。