Chronic Cocaine Exposure & HIV-1 Tat: Dysregulation of the Medical Prefrontal Cor

长期接触可卡因

• 批准号: 7777393
• 负责人: XIU-TI HU
• 金额: $ 14.85万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777393
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; AMPA Receptors; Acquired Immunodeficiency Syndrome; Action Potentials; Affect; Applications Grants; Astrocytes; Behavior Control; Behavioral; Behavioral Model; Biological; Brain; Brain region; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Chronic; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognitive; Comorbidity; Corpus striatum structure; Data; Disease; Dose; Evaluation; Exposure to; Functional disorder; Future; Generations; Glutamate Receptor; Goals; HIV; HIV Infections; HIV tat Protein; HIV-1; Impaired cognition; In Vitro; Individual; Judgment; Lead; Medial; Mediating; Medical; Membrane; Membrane Potentials; Microglia; Morbidity - disease rate; N-Methylaspartate; Nerve Degeneration; Neurocognitive; Neurons; Neuropathogenesis; Nifedipine; Pathogenesis; Pathology; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pilot Projects; Predisposition; Prefrontal Cortex; Process; Proteins; Protocols documentation; Pyramidal Cells; Rattus; Records; Relative (related person); Research Design; Rest; Rewards; Risk; Role; Saline; Slice; Societies; System; Testing; Time; Translating; Up-Regulation; Viral Proteins; Work; addiction; base; channel blockers; cocaine exposure; cognitive function; design; dopamine system; effective therapy; excitotoxicity; hippocampal pyramidal neuron; in vivo; innovation; macrophage; monocyte; mortality; motor deficit; neuroadaptation; neurotoxic; novel; pre-clinical research; progressive neurodegeneration; psychosocial; public health relevance; research study; response; tat Protein; therapeutic target; virotoxins

DESCRIPTION (provided by applicant): Dysregulation and progressive neurodegeneration in the prefrontal cortex of HIV/AIDS patients affect cognitive function and are implicated in HIV-associated neurocognitive disorders (HAND), including HIV- associated dementia (HAD). Although the precise mechanisms that underlie HAD/HAND remain unknown, HIV-1 viral proteins are most likely involved. A prominent example is HIV-1 Tat (Tat), a HIV-1 transactivating protein, causes dysregulation and ultimately death of cortical/striatal neurons and astrocytes in vitro. In the brain, Tat is released by HIV-infected microglia, macrophages and monocytes. The neurotoxic effects of Tat in vitro result from an excessive increase of cytosolic free Ca2+ levels caused by abnormally enhanced Ca2+ influx via L-type Ca2+ channels, activation of ionotropic glutamate receptors and intracellular Ca2+ release. Cocaine abuse increases the morbidity and mortality of HIV/AIDS-associated pathology with exacerbation of cognitive, psychosocial and motor deficits. Even though the medial prefrontal cortex (mPFC) is well- recognized as a critical brain region in the control of these behaviors, as well as of addiction, the mechanisms underlying its dysregulation in the cocaine abuse-HIV/AIDS comorbidity have not been examined. Also, current HIV/AIDS studies predominantly focus on cell cultures, thus, the circuit-related processes are unknown. These two situations have delayed our understanding of the neuropathogenesis of this comorbidity. Our recent work with rats demonstrate that chronic cocaine exposure significantly increases Ca2+ influx by selectively upregulating L-type Ca2+ channel function in pyramidal neurons localized in the mPFC. These novel findings strongly suggest that chronic exposure to cocaine in vivo may potentiate the dysregulation and consequent neurodegeneration of the mPFC induced by Tat. Based on these evidences, the objective of the current project is to ascertain a common biological substrate in the mPFC for cocaine abuse on HIV/AIDS. The designed experiments will test the hypothesis that chronic cocaine exposure in vivo increases susceptibility and vulnerability of the mPFC to HIV-1 Tat by increasing Ca2+ influx via L-type Ca2+ channels in pyramidal cells, and these changes contribute to the pathogenesis of cocaine abuse and HAD. This pilot study is innovative and significant because it will provide informative preliminary data pointing to the mechanisms underlying the cocaine abuse-HAD comorbidity. Results from these studies will used to develop a R01 application focusing on this comorbidity and putative therapeutic targets to help treat dually afflicted individuals. PUBLIC HEALTH RELEVANCE: This grant application is titled: "Chronic cocaine exposure & HIV-1 Tat: Dysregulation of the medial prefrontal cortex." Our goal is to explore the mechanisms of the brain and behavioral deficits induced by cocaine abuse and HIV infection. The combination of these two problems results in a much more severe condition, and unfortunately the combination is spreading in our society. This project will determine how a protein (Tat) produced by HIV-infected cells alters activity of neurons in the medial prefrontal cortex. This brain region is involved both in reward and in judgment, and it is compromised in both cocaine addiction and AIDS. We propose that changes in neuronal activity in the medial prefrontal cortex induced by the HIV protein Tat will be potentiated by repeated cocaine exposure. Findings from this study will help us to verify the common target of cocaine abuse and HIV infection, which will be very important for developing more effective treatments for cocaine abuse and HIV-related brain/behavioral deficits.

描述（由申请人提供）：HIV/AIDS患者前额叶皮层的失调和进行性神经退行性影响影响认知功能，并与HIV相关的神经认知障碍（包括HIV相关痴呆症（HAS））有关。尽管基于/手的基础机制仍然未知，但HIV-1病毒蛋白很可能涉及。一个突出的例子是HIV-1 TAT（TAT），一种HIV-1反式激活蛋白，在体外导致皮质/纹状体神经元和星形胶质细胞的失调并最终导致死亡。在大脑中，TAT由HIV感染的小胶质细胞，巨噬细胞和单核细胞释放。 TAT在体外的神经毒性作用是由于通过L型Ca2+通道异常增强的Ca2+涌入引起的胞质无CA2+水平的过度增加，离子型谷氨酸受体的激活和细胞内CA2+释放的激活。可卡因滥用会增加艾滋病毒/艾滋病相关病理的发病率和死亡率，并加剧认知，社会心理和运动缺陷。即使内侧前额叶皮层（MPFC）在控制这些行为以及成瘾方面被公认为是关键的大脑区域，但尚未检查其在可卡因滥用HIV/AIDS合并症中的机制，但尚未检查其失调的机制。同样，当前的艾滋病毒/艾滋病研究主要集中在细胞培养上，因此，与电路相关的过程尚不清楚。这两种情况延迟了我们对这种合并症的神经病发生的理解。我们最近与大鼠的工作表明，慢性可卡因暴露可通过选择性上调在MPFC中定位的锥体神经元中的L型Ca2+通道功能来显着增加Ca2+流入。这些新颖的发现强烈表明，体内可卡因的长期暴露可能会增强TAT诱导的MPFC的失调和随之而来的神经变性。基于这些证据，当前项目的目的是确定MPFC中可卡因滥用艾滋病毒/艾滋病中常见的生物底物。设计的实验将检验以下假设：慢性可卡因在体内暴露在体内增加了MPFC对HIV-1 TAT的易感性和脆弱性，通过增加锥体细胞中L型Ca2+通道的Ca2+涌入来增加HIV-1 TAT的脆弱性，这些变化对可卡因滥用和可卡因的病原体有影响。这项试点研究具有创新性和重要意义，因为它将提供信息的初步数据，指向可卡因滥用 - 合并症的机制。这些研究的结果将用于开发R01应用程序，以这种合并症和推定的治疗靶标，以帮助治疗双重折磨的个体。公共卫生相关性：该赠款申请的标题为：“慢性可卡因暴露和HIV-1 TAT：内侧前额叶皮层的失调”。我们的目标是探索可卡因滥用和艾滋病毒感染引起的大脑和行为缺陷的机制。这两个问题的结合导致了更严重的状况，不幸的是，这种组合正在我们的社会中蔓延。该项目将决定HIV感染细胞产生的蛋白质（TAT）如何改变内侧前额叶皮层中神经元的活性。这个大脑区域既参与奖励和判断力，并且在可卡因成瘾和艾滋病中都受到妥协。我们提出，HIV蛋白TAT诱导的内侧前额叶皮层中神经元活性的变化将通过重复的可卡因暴露增强。这项研究的结果将有助于我们验证可卡因滥用和艾滋病毒感染的共同靶标，这对于为可卡因滥用和与HIV相关的大脑/行为缺陷开发更有效的治疗非常重要。