Synergistic neurotoxicity of speedball and HIV toxins

描述(由申请者提供)：这项建议通过寻求更好地了解病毒蛋白和多药滥用在艾滋病毒神经认知障碍(HAND)发展中的作用，解决了艾滋病毒-1流行的一个关键方面。艾滋病毒迅速进入大脑，感染巨噬细胞和小胶质细胞，而不是神经元。虽然HAART可以有效地控制这种复制，但手部发病率并没有同时降低，这表明病毒复制并不是所有神经病理的原因。即使在病毒抑制期间，可能来自受感染星状病毒的病毒蛋白也被认为直接或间接地导致神经元损伤。个别滥用药物，如可卡因或吗啡，通过对星形胶质细胞的影响与病毒毒素协同作用，加剧炎症和氧化应激。然而，在美国，多药滥用在药物滥用者中占主导地位，到目前为止，还没有研究检查药物与艾滋病毒神经毒素的组合。这项提议的第一个目标是更好地了解多药滥用(快球)和艾滋病毒神经毒素之间的潜在协同作用。第二个目标是开发一种快速球大鼠模型，以研究使用这些病毒毒素滥用多种药物对运动和记忆的影响。这些目标将通过使用速球和TAT或VPR应用于星形胶质细胞和神经元的体外原代培养来实现，以研究氧化应激和炎症加剧作为协同神经毒性的可能机制。此外，用可卡因、吗啡或速球治疗的大鼠将接受运动和记忆功能评估，随后将对促氧化环境和神经元损伤和死亡进行尸检组织学分析。这项研究将有助于更好地理解病毒毒素和多种药物滥用在产生氧化应激和炎症方面的重叠作用，这似乎是理解手的发育和进展的关键。此外，这项工作将产生一个重要的新工具，在生物学环境中研究艾滋病毒神经认知障碍中发生的运动和记忆缺陷的程度和性质，包括氧化剂的机械作用。这一模式有望有助于设计转化性研究，以发现新的治疗策略，以防止药物滥用环境中手部的发展和进展。公共卫生相关性：在美国，HIV-1感染和药物滥用是两个重要的医学和社会问题。这些流行病独立存在，但也有显著重叠，包括可能对神经认知障碍的协同作用。这项建议旨在更好地界定和了解药物滥用和艾滋病毒感染对神经病理学的综合影响，并产生基线数据，以便能够对艾滋病毒和药物对神经艾滋病的贡献进行有针对性的体内研究。这些信息可用于改善长期管理和减少与这些疾病相关的发病率。

DESCRIPTION (provided by applicant): This proposal addresses a critical aspect of the HIV-1 epidemic by seeking to better understand the roles of viral proteins and polydrug abuse on the development of HIV neurocognitive disorders (HAND). HIV quickly enters the brain and infects macrophages and microglia rather than neurons. While HAART can effectively control this replication, HAND prevalence is not reduced in parallel, indicating that virus replication is not responsible for all neuropathology. Viral proteins that may come from infected astroctyes even during viral suppression are thought to cause neuronal damage both directly and indirectly. Individual drugs of abuse, such as cocaine or morphine, synergize with viral toxins through effects on astrocytes to exacerbate inflammation and oxidative stress. However, polydrug use predominates among substance abusers in the US and no studies to date have examined the combinations of drugs with HIV neurotoxins. The first aim of this proposal is targeted to better understand the potential synergy between polydrug abuse (speedball) and HIV neurotoxins. A second aim is to develop a rat model of speedball to study the motor and memory effects of polydrug abuse with these virotoxins. These goals will be approached using application of speedball and Tat or Vpr to in vitro primary cultures of astrocytes and neurons to study exacerbated oxidative stress and inflammation as a possible mechanism for synergistic neurotoxicity. In addition, rats treated with cocaine, morphine or speedball will be assessed for motor and memory function followed by post mortem histological analyses of prooxidant environment and neuronal damage and death. This research will lead to a better understanding of the overlapping roles of viral toxins and multiple drug abuse in generating oxidative stress and inflammation that appear to be a key to understanding the development and progression of HAND. In addition, the work will generate an essential new tool to study, in a biological setting, the extent and nature of the motor and memory defects that occur in HIV neurocognitive disorders, including the mechanistic role of oxidants. This model is expected to be instrumental in the design of translational studies for discovery of new treatment strategies to prevent HAND development and progression in a drug abuse setting. PUBLIC HEALTH RELEVANCE: HIV-1 infection and drug abuse are two medically and socially important issues in the US. These epidemics exist independently, but also have significant overlap including a possible synergistic contribution to neurocognitive disorders. This proposal seeks to better define and understand the combined effects of drug abuse and HIV infection in neuropathology, as well as to generate baseline data on to permit targeted in vivo studies of the contributions of HIV and drugs to NeuroAIDS. Such information can be used to improve long term management and reduce the morbidity associated with these illnesses.