HIV gp120 and Prefrontal Cortical Function

HIV gp120 和前额皮质功能

基本信息

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
项目类别：
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

项目摘要

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 神经病理学动物模型，可用于评估：1) 认知功能，2) 前额皮质神经元和非神经元变性，3) ）前额皮质网络中细胞和电路的电生理特性。随着改进的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可控制的慢性疾病。这一趋势导致了越来越大的长期接触艾滋病毒神经毒素和艾滋病毒治疗干预的老年人口。虽然有优秀的组织培养模型可用于研究 HIV 或 HIV 治疗对细胞过程的影响，但体内研究 HIV 感染或慢性抗逆转录病毒治疗的影响的选择更加有限，特别是因为它们与大脑老化有关。研究此类问题的理想模型将提供机会来检查认知表现，并将其与整个衰老过程中神经功能和神经病理学的电生理指标以及艾滋病毒感染的发作和随后疾病过程的进展相关联。本提案中概述的工作将重点关注成年和老年大鼠中枢神经系统暴露于 HIV 包膜蛋白 gp120 及其对 1) 两项前额皮质依赖性行为任务的表现，2) 前额皮质回路中的神经元兴奋性和突触传递的影响3) 前额皮质神经元和非神经元细胞的神经毒性损伤程度。这项研究最重要的方面是开发一种动物模型，该模型将有利于大量额外的体内研究，重点关注与 HIV 感染及其治疗相关的广泛潜在药物和机制、这些事件的时间进程以及它们对衰老大脑的影响。特别是，该模型将有助于识别和开发用于成人和老年艾滋病毒/艾滋病患者治疗干预的新靶点和新化合物。在所有询问中，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正常功能的相关性。