HIV gp120 and Prefrontal Cortical Function

HIV gp120 和前额皮质功能

• 批准号: 8331029
• 负责人: Wen-Jun Gao
• 金额: $ 23.18万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331029
• 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. PUBLIC HEALTH RELEVANCE: The goal of this multi-investigator project is to develop a model of HIV neuropathology that can be used to assess: 1) executive function in behaving animals, 2) neuronal and non-neuronal degeneration in the prefrontal cortex (PFC) and 3) electrophysiological properties of cells and circuits in PFC networks. Studies will be conducted in adult and aging rats. Specific experiments will focus on CNS exposure to the HIV envelope protein gp120 and characterize its impact on: 1) performance of two PFC-dependent behavioral tasks, 2) neuronal excitability and synaptic transmission in the PFC circuitry and 3) the degree of neurotoxic insult to neuronal and non-neuronal cells in the PFC. The proposed model 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.

描述（由申请人提供）：这个多感染者项目的目的是开发可用于评估的HIV神经病理学模型：1）认知功能，2）前额叶皮层中的神经元和非神经元变性，以及3）细胞和前环网络中细胞生理学特性。随着改善联合抗逆转录病毒疗法的出现，艾滋病毒感染已从致命疾病转变为慢性可管理状况。这种趋势导致了越来越大的 长期暴露于HIV神经毒素和HIV治疗干预措施的年龄衰老的个体人群。尽管有出色的组织培养模型来研究HIV或HIV疗法对细胞过程的影响，但体内研究对HIV感染或慢性抗逆转录病毒疗法的影响的选择更加有限，尤其是在与大脑衰老有关的情况下。研究此类问题的理想模型将提供机会检查和将认知性能与衰老连续体的神经功能和神经病理学的电生理学指数相对于HIV感染的发作以及随之而来的疾病过程的发展。 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皮质。这项研究的最重要方面是开发动物模型，该模型将具有许多其他体内研究的优势，该研究重点是与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以及它们对衰老大脑的影响。特别是，该模型将促进成人和衰老艾滋病毒/艾滋病患者治疗干预措施的新靶标和新化合物的鉴定和开发。在所有查询中，该模型将验证体外组织培养研究的发现及其与完整的中枢神经系统中规范功能的相关性。 公共卫生相关性：这个多功能项目的目的是开发一种可用于评估的HIV神经病理学模型：1）行为动物的执行功能，2）前额叶皮质（PFC）和3）细胞和电路的电源性质中的神经元和非神经元变性。研究将在成年大鼠和衰老大鼠中进行。具体的实验将集中于中枢神经系统暴露于HIV包膜蛋白GP120，并表征其对以下方面的影响：1）PFC电路中两个依赖PFC的行为任务的性能，2）神经元的兴奋性和突触传播，以及3）神经毒性的iNVINAL和非神经元和非神经元和非神经元细胞的程度。提出的模型将具有许多其他体内研究的优势，该研究重点是与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以及它们对衰老大脑的影响。