White matter changes in HIV models

HIV模型中白质的变化

基本信息

批准号：
8151109
负责人：
Pamela E Knapp
金额：
$ 18.31万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8151109
关键词：
Acquired Immunodeficiency Syndrome Acute Address Affect Anti-Retroviral Agents Astrocytes Autopsy Biochemical Blood - brain barrier anatomy Blood Vessels Brain Cell Death Cell Line Cell model Chronic Clinical Cognition Disorders Corpus Callosum Corpus striatum structure Defect Dementia Disease Evaluation Exploratory/Developmental Grant Exposure to Extravasation Female Functional disorder Future Gender Glutamates HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Highly Active Antiretroviral Therapy Histology Human Human immunodeficiency virus test Image Immunosuppression In Situ Nick-End Labeling In Vitro Incidence Individual Infection Intervention Lead Life Longevity Magnetic Resonance Imaging Membrane Methods Microglia Modeling Morphology Mus Myelin Myelin Proteins N-Methylaspartate Nature Neuraxis Neurologic Neurologic Deficit Neurologic Dysfunctions Oligodendroglia Outcome Pallor Pathology Patients Pharmaceutical Preparations Population Prevalence Process Process Measure Production Protein Splicing Proteins Reporting Role Severities Signal Transduction Symptoms Testing Therapeutic Thick Toxic effect Transgenic Mice Variant Vasculitis Viral Viral Proteins Work antiretroviral therapy base caspase-3 chemokine cytokine high reward high risk in vivo in vivo Model male motor disorder nerve stem cell neuropathology neurotoxic public health relevance src-Family Kinases therapeutic target trend viral resistance white matter white matter change white matter damage

项目摘要

DESCRIPTION (provided by applicant): Acquired immunodeficiency syndrome, caused by human immunodeficiency virus-1 (HIV-1) infection, is the most common cause of dementia in non-aged individuals in the US. Highly active, or combined, antiretroviral therapy (HAART or cART) has controlled viral replication and immunosuppression, and initially reduced the severity of neurologic disease. However, with increased patient lifespan the prevalence of more moderate cognitive and motor disease has increased. Most AIDS patients now develop neurologic and/or psychiatric symptoms during their disease course, and pathology is seen in most brains at autopsy. There is also an increasing incidence of dementia in patients receiving HAART, attributed to emergence of neurovirulent strains, to viral resistance, or to long-term CNS exposure to toxic, therapeutics. HIV neuropathology thus remains a serious clinical problem. What is the basis of HIV neurologic deficits? HIV proteins such as gp120, Tat, Vpr and Nef are directly neurotoxic, and may also modulate indirect toxicity by causing functional changes in astroglia and microglia (ex: chemo/cytokine secretion, [Ca2+]i destabilization). Damage to myelin or oligodendrocytes (OLs), would enhance neurologic dysfunction. "Myelin pallor" is an anomaly consistently reported in HIV patients. It was historically attributed to vasculitis and subsequent blood brain barrier leakage. Even if vasculitis is involved in myelin pallor, OLs/myelin may also be more immediate targets of viral proteins, since white matter defects are observed when myelin pallor is absent. Our central hypothesis is that chronic exposure to HIV proteins causes direct damage to OLs and/or myelin. To support the hypothesis, we showed that even short periods of Tat induction in a transgenic mouse caused caspase-3 expression, and abnormal morphology and ultrastructure in OLs. The findings after acute exposure suggest that chronic exposures typical in HIV patients may further damage OLs and myelin and contribute to neurologic dysfunction. This R21 proposal contains in vivo studies that assess the extent and character of white matter and OL/myelin damage after chronic exposure (6 months) to HIV-1 Tat. Aim 1 tests the hypothesis that chronic exposure causes escalating damage to OLs and myelin, using biochemical, stereological, and ultrastructural methods. The effect of gender is examined as a critical variable. Aim 2 uses in vitro methods to test the hypothesis that OLs are direct targets of Tat and of HIV. Studies address potential mechanisms that may lead to interventions. All results are correlated with MRI studies of chronic exposure that are already underway. PUBLIC HEALTH RELEVANCE: HIV infection causes central nervous system dysfunction, even in patients receiving anti-retroviral therapy. With longer patient lifespans, the prevalence of neurologic dysfunction in HIV has increased in recent years. White matter abnormalities, assessed by imaging or histology, are reported in many HIV patients. White matter defects may contribute to symptoms, and may also represent a therapeutic target. This project uses a chronic in vivo model of HIV protein exposure to systematically describe components of white matter damage in males and females. Culture studies with viral protein and HIV test whether oligodendrocytes are directly affected.

描述（由申请人提供）：由人类免疫缺陷病毒-1（HIV-1）感染引起的获得的免疫缺陷综合征，是美国非年龄个体痴呆症的最常见原因。高度活跃或组合的抗逆转录病毒疗法（HAART或CART）具有控制病毒复制和免疫抑制，最初降低了神经系统疾病的严重程度。但是，随着患者寿命的增加，更中等认知和运动疾病的患病率增加了。现在，大多数艾滋病患者在病原体过程中出现神经系统和/或精神病症状，并且在尸检时大脑中都可以看到病理学。接受HAART的患者的痴呆症发生率也越来越多，这是由于神经毒素菌株的出现，病毒抗性的，或长期暴露于有毒，治疗药物的CNS。因此，HIV神经病理学仍然是一个严重的临床问题。 HIV神经系统缺陷的基础是什么？ HIV蛋白（例如GP120，TAT，VPR和NEF）是直接神经毒性的，也可能通过引起星形胶质细胞和小胶质细胞的功能变化来调节间接毒性（例如：化学/细胞因子分泌，[CA2+] I DeTabilization）。对髓磷脂或少突胶质细胞（OLS）的损害会增强神经功能障碍。 “髓磷脂”是艾滋病毒患者始终报道的一种异常。从历史上看，它归因于血管炎和随后的血脑屏障泄漏。即使血管炎与髓磷脂苍白有关，OLS/髓磷脂也可能是病毒蛋白的直接靶标，因为当缺乏髓磷脂苍白时观察到白质缺陷。我们的中心假设是，长期暴露于HIV蛋白会对OLS和/或髓磷脂造成直接损害。为了支持该假设，我们表明，即使是转基因小鼠中的TAT诱导短期，也会引起caspase-3表达，OLS中的异常形态和超微结构。急性暴露后的发现表明，HIV患者典型的慢性暴露可能会进一步损害OLS和髓磷脂，并导致神经功能障碍。该R21提案包含体内研究，可评估慢性暴露（6个月）对HIV-1 TAT后白质和OL/髓磷脂损伤的程度和特征。 AIM 1检验了以下假设：使用生化，立体和超微结构方法，慢性暴露会导致对OLS和髓磷脂的损害升级。性别的效果被检查为关键变量。 AIM 2使用体外方法来检验OLS是TAT和HIV的直接靶标的假设。研究解决了可能导致干预措施的潜在机制。所有结果与已经在进行的慢性暴露的MRI研究相关。公共卫生相关性：即使在接受抗逆转录病毒疗法的患者中，HIV感染也会引起中枢神经系统功能障碍。随着患者寿命的较长，近年来，艾滋病毒神经功能障碍的患病率有所增加。在许多HIV患者中，通过成像或组织学评估的白质异常。白质缺陷可能导致症状，也可能代表治疗靶点。该项目使用慢性在体内模型的HIV蛋白暴露于系统地描述男性和女性中白质损害的成分。病毒蛋白和艾滋病毒的培养研究是否直接影响少突胶质细胞。