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

• 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
• 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

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）：尽管出现了高效抗逆转录病毒治疗（HAART），但HIV-1感染通常导致神经系统问题的发展。此外，艾滋病毒感染经常与使用成瘾药物有关，如甲基苯丙胺（METH）。虽然HIV-1和METH都可以引起行为，神经认知和组织病理学变化，但病毒，HAART和METH的潜在相互作用知之甚少，特别是在细胞和分子水平上，将在这里进行研究。甲基苯丙胺和艾滋病毒损害了几种神经递质系统的功能。HIV-1包膜蛋白gp 120通过CD 4和趋化因子共受体与巨噬细胞和小胶质细胞结合。HIV/gp 120在体外和体内产生神经元损伤和死亡，并且在其脑中表达gp 120的转基因小鼠产生与AIDS患者相似的神经病理学特征。因此，中心假设是METH的使用使HIV-1感染的神经毒性恶化，从而损害HAART对HIV感染的有益作用和HIV相关神经认知障碍的发展。长期目标是改善神经艾滋病的治疗干预。具体目标是：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。为此目的，我们将用METH、HAART、HIVgp 120和载体对照的组合来治疗皮质神经元，并评估神经元损伤、损失和存活、电生理功能、细胞内Ca 2+对兴奋性神经递质的响应以及神经元对兴奋性毒性损伤的脆弱性。将使用TUNEL染色的核DNA显微镜检查结合神经元标记物的免疫染色来监测神经元死亡和丢失。蛋白质、脂质和DNA的氧化以及活性半胱天冬酶3将作为细胞应激和死亡信号传导的标志物进行监测。METH、HAART和gp 120在各种组合中对通过应激激酶p38 MAPK和促生存激酶Akt的信号转导的潜在作用可能对增强HIV/gp 120诱导的神经毒性至关重要，并将使用这两种激酶的显性阴性突变体进行研究。 公共卫生相关性：尽管进行了高效抗逆转录病毒治疗（HAART），但HIV-1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接触成瘾药物有关，如甲基苯丙胺（METH），两者都是主要的公共卫生问题。我们的研究将提高对HAART存在下METH和HIV感染联合引起的脑损伤的理解。