Dopamine Systems and Neuropsychiatric Changes in HIV/AIDS

多巴胺系统和艾滋病毒/艾滋病的神经精神变化

基本信息

批准号：
7880874
负责人：
BENJAMIN B. GELMAN
金额：
$ 24.38万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-25 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7880874
关键词：
AIDS Dementia Complex AIDS neuropathy AIDS/HIV problem Addictive Behavior Address Alternative Splicing Astrocytes Autopsy Axon Behavior Behavioral Biochemical Biological Assay Blood Brain Brain Stem CD4 Positive T Lymphocytes Cells Cerebrospinal Fluid Clinical Clinical Management Clinical Virology Comorbidity Corpus striatum structure DNA DRD2 gene Data Databases Disease Dopamine Dopamine Receptor Drug abuse Dynorphins Encephalitis Enkephalins Fiber Functional disorder GTP-Binding Proteins HIV HIV Core Protein p24 HIV Infections HIV encephalitis HIV-1 Hepatitis C High Prevalence Immunology Impairment Link Lymphocyte Subset Major Depressive Disorder Mental Depression Mood Disorders Motor National NeuroAids Tissue Consortium Nerve Nerve Degeneration Neurobiology Neurocognitive Neurologic Neuropeptides Neurotransmitters Nodule Phosphorylation Plasma Presynaptic Terminals Property Protein Binding Protein Isoforms Proteins Psychotic Disorders RNA Recording of previous events Research Personnel Rewards Specimen Staining method Stains Substance abuse problem Substance of Abuse Synapses Synaptic Transmission System Tissues Transcript Tyrosine 3-Monooxygenase Variant addiction antiretroviral therapy base clinically significant cocaine use cohort dopamine system frontal lobe frontal lobe function neural circuit neurochemistry neuroinflammation neuropsychiatry neuropsychological presynaptic programs protein expression relating to nervous system reuptake transmission process

项目摘要

DESCRIPTION (provided by applicant): This project will elucidate the neurochemical mechanism and clinical implications of abnormal dopaminergic (DAergic) synaptic transmission in people with HIV/AIDS. The concept follows from original preliminary data that have established that DAergic synapses are biochemically abnormal in people with HIV-associated dementia and HIV encephalitis (HIVE). Abnormal DAergic transmission is related to neurocognitive impairment, psychosis, depression, addictive behavior and motor slowing. All of those problems occur with high prevalence in people with HIV/AIDS. To determine the clinical significance of abnormal DAergic transmission in HIV/AIDS, we will perform a circuit-level biochemical analysis of autopsy brain specimens. The baseline aim will determine whether HIV encephalitis (HIVE) is required to produce abnormal DAergic synapses and, whether or not the anomaly is related to virological and immunological changes in blood and CSF. A second aim will address important clinical implications of abnormal DAergic synapses, including involvement in frontal lobe dysfunction, drug abuse, psychosis, and mood disorders. In those studies, specific DAergic circuits that drive abnormal behavior will be isolated and studied. The final aim addresses the pathophysiology of abnormal DAergic systems, to include the neuropathological, neurovirological, neurochemical and neuroimmunological aspects. We also will evaluate the influence of comorbid conditions that can produce neurological changes, including hepatitis C virus infection and antiretroviral therapies. The analysis will be done with brain specimens from the National NeuroAIDS Tissue Consortium (NNTC). The NNTC database contains detailed information regarding neuropsychological changes, substance abuse, comorbid factors, clinical virology and immunology of the decedents. Our results would provide the neuroAIDS field with bedrock neurochemical and neuropathological data on abnormal DAergic systems, and address correlations with many clinical problems and comorbidities of the people with HIV/AIDS. The neurobiological "blueprint" that we will pursue will help formulate strategies for clinical management of DAergic dysfunction, including its potential influence on frontal lobe dysfunction and neuropsychiatric disorders. The project breaks ground neuroscientifically, as no autopsy study has advanced to a "task specific" behavioral correlation with circuit level anomalies of a specific neurotransmitter system.

描述（由申请人提供）：该项目将阐明艾滋病毒/艾滋病患者中多巴胺能（DAERPIC）突触传播异常的神经化学机制和临床意义。该概念来自原始的初步数据，这些数据已经确定Daergic突触在患有HIV相关痴呆症和HIV脑炎（Hive）的患者中是生化异常的。 DAergic传播异常与神经认知障碍，精神病，抑郁，成瘾行为和运动放缓有关。所有这些问题都出现在艾滋病毒/艾滋病患者中的高流行率。为了确定艾滋病毒/艾滋病异常daergic传播的临床意义，我们将对尸检大脑样本进行电路级生化分析。基线目标将确定HIV脑炎（HIVE）是否需要产生异常的DAERAGES突触，以及该异常是否与血液和CSF的病毒学和免疫学变化有关。第二个目的将解决异常Daergic突触的重要临床意义，包括参与额叶功能障碍，药物滥用，精神病和情绪障碍。在这些研究中，将分离和研究驱动异常行为的特定Daergic电路。最终目的旨在解决异常的daergic系统的病理生理，包括神经病理学，神经病毒学，神经化学和神经免疫学方面。我们还将评估可以产生神经系统变化的合并症的影响，包括丙型肝炎病毒感染和抗逆转录病毒疗法。该分析将使用来自国家神经辅助组织（NNTC）的脑标本进行。 NNTC数据库包含有关神经心理学变化，药物滥用，合并因素，临床病毒学和免疫学的详细信息。我们的结果将为神经辅助领域提供有关异常DAergic系统的基岩神经化学和神经病理学数据，并解决与艾滋病毒/艾滋病患者的许多临床问题和合并症有关的相关性。我们将追求的神经生物学“蓝图”将有助于制定策略来临床管理DAERFIC功能障碍，包括其对额叶功能障碍和神经精神疾病的潜在影响。该项目构成了地面神经科学的影响，因为没有尸检研究升至与特定神经递质系统的电路水平异常的“任务特定”行为相关性。