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HIV TAT protein in nicotine dependence

尼古丁依赖中的 HIV TAT 蛋白

基本信息

批准号：
8607925
负责人：
Svetlana Semenova
金额：
$ 15.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607925
关键词：
Abstinence Acquired Immunodeficiency Syndrome Affective Anhedonia Animal Model Anti-Retroviral Agents Applications Grants Area Behavioral Biological Markers Brain Brain Injuries Cell Fractionation Cell membrane Cells Centers for Disease Control and Prevention (U.S.)Chronic Cocaine Corpus striatum structure Cues DNA Development Doxycycline Environment Exhibits Exposure to Functional disorder Future General Population HIV HIV Infections HIV Seropositivity HIV-1 High Prevalence Human Immunohistochemistry Individual Injection of therapeutic agent Knowledge Lead Maintenance Measures Methods Morbidity - disease rate Motivation Mus Nerve Degeneration Neurons Nicotine Nicotine Dependence Nicotine Withdrawal Nicotinic Receptors Nucleus Accumbens Pathology Pathway interactions Patients Pattern Pharmaceutical Preparations Population Prefrontal Cortex Prevalence Procedures Property Proteins Research Rewards Risk Role Self Stimulation Smoker Smoking Source Stimulus Structure System Tobacco Tobacco smoking Transgenic Mice Transgenic Organisms Travel Tyrosine 3-Monooxygenase Ventral Tegmental Area Vesicle Viral Viral Genome Viral Nonstructural Proteins Withdrawal Withdrawal Symptom Work brain tissue craving dopamine transporter drug reward effective therapy improved macrophage mortality mouse model neurobiological mechanism neurochemistry neuropathology neurotoxic preference protein expression response reward processing transmission process

项目摘要

DESCRIPTION (provided by applicant): The disproportionally higher levels of nicotine dependence among HIV-infected individuals compared to the general population may indicate altered sensitivity to nicotine and nicotine withdrawal in smokers with HIV. Altered sensitivity to nicotine may result from HIV-induced damage to corticolimbic brain structures and dysregulation of major transmitter systems critically involved in reward processes, in particular dopaminergic (DA) transmission. Thus, there is a critical need to investigate the neurobiological mechanisms underlying nicotine dependence in HIV-infected humans. HIV-induced neurodegeneration involves, in part, neurotoxic viral products including the HIV-1 TAT, a viral nonstructural protein that is critical for viral replication and is secreted by HIV-infected cells. TAT has been found in the brain of HIV-1 post-mortem brain tissue. The proposed studies will be conducted on a doxycycline (Dox)-inducible and brain targeted HIV-1 TAT transgenic mouse model, TAT- induced (iTAT) mice. This mouse model with induced TAT expression is a well-accepted animal model of HIV- related pathology. The TAT protein induces neurodegeneration and dysfunction in the mesocorticolimbic DA system in mice similar to HIV-induced pathology seen in humans. Importantly, the iTAT mouse model allows one to expose mice to nicotine before the induction of TAT expression, and continue nicotine exposure concurrently with TAT expression to mimic the human condition of smoking before and during HIV infection. Limited evidence indicates that TAT expression potentiates cocaine reward and leads to increased DA transporter levels in the striatum, suggesting altered sensitivity to drug reward. The role of TAT expression in nicotine reward and nicotine withdrawal is unknown. There are several sources of motivation that contribute to the maintenance of nicotine dependence including the environment or conditioned cues associated with nicotine reward and the negative consequences of nicotine withdrawal. The proposed studies will characterize two aspects of nicotine dependence in iTAT mice such as the conditioned rewarding effects of nicotine (Specific Aim 1) and affective/somatic aspects of nicotine withdrawal (Specific Aim 2). Neurochemical studies will investigate changes in DA transmission in corticolimbic brain areas in response to nicotine and nicotine withdrawal (Specific Aim 3). It is predicted that iTAT mice will show higher sensitivity to conditioned rewarding effects of nicotine and exacerbated affective/somatic aspects of nicotine withdrawal. TAT-expression will also result in DA terminal damage as reflected in altered levels of biomarkers of DA transmission (DA transporter and tyrosine hydroxylase). This pattern of results will support the hypothesis that HIV-infected individuals may have altered DA transmission resulting in enhanced sensitivity to the reinforcing effects of nicotine and more pronounced withdrawal symptoms during abstinence from nicotine, leading to the high smoking rates in this population. Understanding the effects of TAT expression may help identify a target for development of preventative or adjunct therapies for the treatment of nicotine dependence in the HIV-infected population.

描述（由申请方提供）：与一般人群相比，HIV感染者的尼古丁依赖水平明显较高，这可能表明HIV吸烟者对尼古丁的敏感性和尼古丁戒断发生了改变。改变了对尼古丁可能是由于HIV引起的皮质边缘脑结构的损伤和与奖赏过程特别是多巴胺能（DA）传递密切相关的主要递质系统的失调。因此，迫切需要研究艾滋病毒感染者尼古丁依赖的神经生物学机制。HIV诱导的神经变性部分涉及神经毒性病毒产物，包括HIV-1达特，一种病毒非结构蛋白它对病毒复制至关重要，由艾滋病毒感染细胞分泌。达特已被发现， HIV-1死后的大脑组织拟定的研究将在多西环素（Dox）诱导和脑靶向HIV-1达特转基因小鼠模型达特诱导（iTAT）小鼠中进行。这种具有诱导达特表达的小鼠模型是HIV相关病理学的公认动物模型。达特蛋白诱导小鼠中皮质边缘DA系统的神经变性和功能障碍，类似于在人类中观察到的HIV诱导的病理学。重要的是，iTAT小鼠模型允许在诱导达特表达之前将小鼠暴露于尼古丁，并在达特表达的同时继续尼古丁暴露，以模拟HIV感染之前和期间的人类吸烟状况。有限的证据表明，达特的表达增强可卡因的奖励，并导致增加多巴胺转运蛋白水平在纹状体，这表明改变敏感性药物奖励。达特表达在尼古丁奖赏和尼古丁戒断中的作用尚不清楚。有几个动机来源有助于维持尼古丁依赖，包括与尼古丁奖励相关的环境或条件暗示以及尼古丁戒断的负面后果。拟定的研究将表征iTAT小鼠尼古丁依赖的两个方面，例如尼古丁的条件性奖励效应（具体目标1）和尼古丁戒断的情感/躯体方面（具体目标2）。神经化学研究将研究皮质边缘脑区中DA传递对尼古丁和尼古丁戒断反应的变化（具体目标3）。据预测，iTAT小鼠将显示出对尼古丁的条件性奖励效应的更高敏感性，并加剧尼古丁戒断的情感/躯体方面。TAT表达还将导致DA末端损伤，如DA传递的生物标志物（DA转运蛋白和酪氨酸羟化酶）的水平改变所反映的。这种结果模式将支持这样的假设，即HIV感染者可能改变了DA的传播，导致对尼古丁的增强作用的敏感性增强，在戒烟过程中出现更明显的戒断症状，从而导致该人群的高吸烟率。了解达特表达的影响可能有助于确定HIV感染人群尼古丁依赖治疗的预防性或辅助疗法的发展目标。