HIV gp120 and Prefrontal Cortical Function

HIV gp120 和前额皮质功能

• 批准号: 8434874
• 负责人: Wen-Jun Gao
• 金额: $ 18.54万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434874
• 关键词: AIDS/HIV problem; Adult; Affect; Aging; Animal Model; Animals; Attention; Behavioral; Catecholamines; Cell Death; Cell physiology; Cells; Chronic; Cognitive; Confocal Microscopy; Development; Disease; Dopamine; Electrophysiology (science); Event; Exhibits; Exposure to; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV therapy; HIV-1; Image Analysis; Immunohistochemistry; In Vitro; Individual; Infusion procedures; Investigation; Laboratories; Link; Membrane; Methylphenidate; Modeling; Morphology; Nerve Degeneration; Neuraxis; Neuroglia; Neurons; Neurophysiology - biologic function; Neurotoxins; Norepinephrine; Patients; Performance; Pharmaceutical Preparations; Physiological; Population; Prefrontal Cortex; Process; Property; Rattus; Research Personnel; Ritalin; Rodent; Specific qualifier value; Structure; Study models; Synapses; Synaptic Transmission; Techniques; Therapeutic Intervention; Time; Tissues; Virus; Work; aged; aging brain; animal model development; antiretroviral therapy; brain tissue; cognitive function; env Gene Products; executive function; flexibility; hippocampal pyramidal neuron; improved; in vivo; indexing; neuronal excitability; neuropathology; neurotoxic; postsynaptic; psychostimulant; research study; senescence; tissue culture; transmission process; trend

DESCRIPTION (provided by applicant): The goal of this multi-investigator project is to develop an animal model of HIV neuropathology that can be used to assess: 1) cognitive function, 2) neuronal and non-neuronal degeneration in the prefrontal cortex and 3) electrophysiological properties of cells and circuits in prefrontal cortical networks. With the advent of improved combination antiretroviral therapy, HIV infection has been transformed from a fatal illness to a chronic manageable condition. This trend has resulted in an increasingly large population of aging individuals with prolonged exposure to HIV neurotoxins and to HIV therapeutic interventions. While there are excellent tissue culture models for studying the impact of HIV or HIV therapy on cellular processes, the options for in vivo investigation of the effects o HIV infection or chronic antiretroviral therapy are more limited, particularly as they relate to th aging brain. The ideal model for investigating such issues would provide the opportunity to examine and correlate cognitive performance with electrophysiological indices of neural function and neuropathology across the aging continuum with respect to onset of the HIV infection and progression of ensuing disease processes. The work outlined in this proposal will focus on CNS exposure to the HIV envelope protein gp120 in adult and aged rats and its impact on 1) performance of two prefrontal cortex-dependent behavioral tasks, 2) neuronal excitability and synaptic transmission in the prefrontal cortical circuitry and 3) the degree of neurotoxic insult t neuronal and non-neuronal cells in the prefrontal cortex. The most important aspect of this investigation is the development of an animal model that will have advantages for numerous additional in vivo studies focusing on the broad array of potential agents and mechanisms associated with HIV infection and its treatment, the time course of these events, and their impact on the aging brain. In particular this model will facilitate the identification and development of new targets and new compounds for therapeutic interventions in adult and aging HIV/AIDS patients. Across all inquiries, the model will validate the findings of in vitro tissue culture studies and their relevance to normative functions in the intact central nervous system.

描述（由申请人提供）：这个多研究者项目的目标是开发一种HIV神经病理学的动物模型，可用于评估：1）认知功能，2）前额叶皮质的神经元和非神经元变性和3）前额叶皮质网络中细胞和电路的电生理特性。随着改进的抗逆转录病毒综合疗法的出现，艾滋病毒感染已从一种致命疾病转变为一种可控制的慢性疾病。这一趋势导致了越来越大的 长期暴露于艾滋病毒神经毒素和艾滋病毒治疗干预措施的老年人群体。虽然有很好的组织培养模型用于研究HIV或HIV治疗对细胞过程的影响，但用于体内研究HIV感染或慢性抗逆转录病毒治疗的影响的选择更为有限，特别是当它们涉及衰老大脑时。调查这些问题的理想模型将提供机会，检查和相关的认知性能与神经功能和神经病理学的电生理指标在整个老化连续体的艾滋病毒感染和随后的疾病过程的进展方面的发病。本提案中概述的工作将侧重于成年和老年大鼠CNS暴露于HIV包膜蛋白gp 120及其对以下方面的影响：1）两项前额叶皮质依赖性行为任务的表现，2）前额叶皮质回路中的神经元兴奋性和突触传递，3）前额叶皮质中神经元和非神经元细胞的神经毒性损伤程度。这项研究的最重要的方面是开发一种动物模型，该模型将有利于许多额外的体内研究，重点是与HIV感染及其治疗相关的广泛的潜在药物和机制，这些事件的时间过程及其对衰老大脑的影响。特别是，这一模式将有助于确定和开发新的目标和新的化合物，用于成年和老年艾滋病毒/艾滋病患者的治疗干预。在所有调查中，该模型将验证体外组织培养研究的结果及其与完整中枢神经系统中规范功能的相关性。