Combined effect of Methamphetamine, HIV and HAART on neurons and macrophages

甲基苯丙胺、HIV 和 HAART 对神经元和巨噬细胞的联合作用

基本信息

批准号：
8049237
负责人：
MARCUS KAUL
金额：
$ 18.53万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
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：
2010-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8049237
关键词：
AIDS Dementia Complex AIDS neuropathy Acquired Immunodeficiency Syndrome Adherence Affect Anti-Retroviral Agents Behavioral Binding Biological Process Brain Brain Injuries CCR5 gene CXCR4 gene Cells Cellular Stress Cessation of life Clinical DNA Dementia Development Disease Dominant-Negative Mutation Exposure to HIV HIV Envelope Protein gp120 HIV-1 Highly Active Antiretroviral Therapy Immune Impaired cognition In Situ Nick-End Labeling In Vitro Incidence Infection Link Lipids Lymphocyte MAP Kinase Gene MAPK14 gene Methamphetamine Microglia Microscopy Mitochondria Molecular Monitor Motor Neuraxis Neurocognitive Neurologic Neuronal Injury Neurons Neurotransmitters Nuclear Patients Pharmaceutical Preparations Phosphotransferases Production Proteins Public Health Risk Factors Serotonin Signal Transduction Staining method Stains Stress Symptoms System Therapeutic Intervention Thymidine Transgenic Mice Viral Viral Load result Viral Proteins Virus Virus Diseases Zidovudine caspase-3 chemokine dopamine transporter env Gene Products improved in vivo macrophage monocyte neurogenesis neurotoxicity oxidation psychostimulant public health relevance receptor recreational drug use response viral DNA

项目摘要

DESCRIPTION (provided by applicant): Infection with HIV-1 often leads to the development of neurological problems despite the advent of highly active antiretroviral therapy (HAART). In addition, HIV-infection is frequently associated with the use of addictive drugs, such as Methamphetamine (METH). While both HIV-1 and METH can cause behavioral, neurocognitive and histopathological changes, the potential interaction of virus, HAART and METH is poorly understood, in particular at the cellular and molecular level, and will be studied here. METH and HIV compromise the function of several neurotransmitter systems. HIV-1 envelope protein gp120 binds to macrophages and microglia via CD4 and chemokine co-receptors. HIV/gp120 produces in vitro and in vivo neuronal injury and death, and transgenic mice expressing gp120 in their brain develop neuropathological features similar to AIDS patients. Thus, the central hypothesis is that use of METH aggravates the neurotoxicity of HIV-1 infection and thus compromises the beneficial effect of HAART against HIV infection and the development of HIV-associated neurocognitive disorders. The long-term objective is to improve therapeutic intervention for neuroAIDS. The specific aim is: To characterize the combined impact of Methamphetamine, HIV-1 and HAART on the biological function and survival of neurons. For that purpose we will treat cerebrocortical neurons with combinations of METH, HAART, HIVgp120 and vehicle controls and assess neuronal injury, loss and survival, electrophysiological function, intracellular Ca2+ in response to excitatory neurotransmitter and neuronal vulnerability to excitotoxic insult. Neuronal death and loss will be monitored using microscopy of TUNEL stained nuclear DNA in combination with immunostaining for neuronal markers. Oxidation of protein, lipid and DNA, and active Caspase 3 will be monitored as markers of cellular stress and death signaling. The potential effect of METH, HAART and gp120 in various combinations on signal transduction via stress kinase p38 MAPK and pro-survival kinase Akt may be crucial to an enhancement of HIV/gp120-induced neurotoxicity and will be studied using dominant negative mutants of both kinases. PUBLIC HEALTH RELEVANCE: Infection with HIV-1 is often leads to neurological complications despite highly active antiretroviral therapy (HAART). Moreover, HIV infection is frequently associated with exposure to addictive drugs, such as Methamphetamine (METH), and both are major public health concerns. Our studies will improve the understanding of brain injury caused by the combination of METH and HIV infection in the presence of HAART.

描述（由申请人提供）：尽管高度活跃的抗逆转录病毒疗法（HAART）出现了HIV-1的感染，通常导致神经系统问题的发展。另外，HIV感染经常与使用上瘾的药物（例如甲基苯丙胺（METH））有关。尽管HIV-1和METH都会引起行为，神经认知和组织病理学的变化，但病毒，HAART和METH的潜在相互作用却鲜为人知，尤其是在细胞和分子水平上，并且将在这里进行研究。甲基和HIV损害了几种神经递质系统的功能。 HIV-1包膜蛋白GP120通过CD4和趋化因子共受体与巨噬细胞和小胶质细胞结合。 HIV/GP120产生体外和体内神经元损伤和死亡，以及在其大脑中表达GP120的转基因小鼠会发展出类似于艾滋病患者的神经病理学特征。因此，中心假设是，使用MET的使用加剧了HIV-1感染的神经毒性，从而损害了HAART对HIV感染的有益作用以及与HIV相关的神经认知疾病的发展。长期目标是改善神经助剂的治疗干预措施。具体目的是：表征甲基苯丙胺，HIV-1和HAART对神经元生物学功能和存活的综合影响。为此，我们将使用甲基，HAART，HIVGP120和车辆控制的组合来治疗脑皮层神经元，并评估神经元损伤，丧失和生存，电生理功能，细胞内Ca2+响应兴奋性神经递质和神经元易受兴奋性毒性毒素的影响。神经元死亡和丧失将使用TUNEL染色核DNA的显微镜与神经元标记的免疫染色相结合来监测。蛋白质，脂质和DNA以及活性caspase 3的氧化将被监测为细胞应激和死亡信号传导的标志。甲基，HAART和GP120在各种组合中对通过应力激酶p38 MAPK和亲生激酶AKT的信号转导的潜在影响可能对增强HIV/GP120诱导的神经毒性的增强至关重要，并将使用两种激酶的显性阴性突变体进行研究。公共卫生相关性：尽管高度活跃的抗逆转录病毒疗法（HAART），患有HIV-1的感染通常会导致神经系统并发症。此外，艾滋病毒感染经常与甲基苯丙胺（甲基苯丙胺）等上瘾药物的暴露有关，两者都是主要的公共卫生问题。我们的研究将提高对HAART存在的甲基苯酚和艾滋病毒感染的组合引起的脑损伤的理解。