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

长期接触可卡因

• 批准号: 7686005
• 负责人: XIU-TI HU
• 金额: $ 15万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686005
• 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 患者前额皮质的失调和进行性神经变性影响认知功能，并与 HIV 相关的神经认知障碍（HAND）有关，包括 HIV 相关的痴呆（HAD）。尽管 HAD/HAND 背后的确切机制仍不清楚，但 HIV-1 病毒蛋白很可能参与其中。一个突出的例子是 HIV-1 Tat (Tat)，一种 HIV-1 反式激活蛋白，在体外会导致皮质/纹状体神经元和星形胶质细胞失调并最终死亡。在大脑中，Tat 由感染 HIV 的小胶质细胞、巨噬细胞和单核细胞释放。 Tat 的体外神经毒性作用是由于通过 L 型 Ca2+ 通道的 Ca2+ 流入异常增加、离子型谷氨酸受体的激活和细胞内 Ca2+ 释放导致胞质游离 Ca2+ 水平过度增加。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、心理和运动缺陷。尽管内侧前额叶皮层（mPFC）被广泛认为是控制这些行为以及成瘾的关键大脑区域，但其在可卡因滥用-艾滋病毒/艾滋病合并症中的失调机制尚未得到研究。此外，目前的艾滋病毒/艾滋病研究主要集中在细胞培养上，因此，与回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发病机制的理解。我们最近对大鼠的研究表明，慢性可卡因暴露通过选择性上调位于 mPFC 的锥体神经元中的 L 型 Ca2+ 通道功能，显着增加 Ca2+ 流入。这些新发现强烈表明，体内长期接触可卡因可能会加剧 Tat 引起的 mPFC 失调和随之而来的神经变性。基于这些证据，当前项目的目标是确定 mPFC 中可卡因滥用与艾滋病毒/艾滋病的共同生物底物。设计的实验将验证以下假设：体内长期接触可卡因会通过锥体细胞中 L 型 Ca2+ 通道增加 Ca2+ 流入，从而增加 mPFC 对 HIV-1 Tat 的易感性和脆弱性，而这些变化有助于可卡因滥用和可卡因滥用的发病机制。有。这项试点研究具有创新性且意义重大，因为它将提供翔实的初步数据，指出可卡因滥用与 HAD 合并症的潜在机制。这些研究的结果将用于开发 R01 应用程序，重点关注这种合并症和假定的治疗目标，以帮助治疗患有双重疾病的个体。公共健康相关性：该拨款申请的标题是：“慢性可卡因暴露与 HIV-1 Tat：内侧前额皮质失调”。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加严重的情况，不幸的是，这种结合正在我们的社会中蔓延。该项目将确定 HIV 感染细胞产生的蛋白质 (Tat) 如何改变内侧前额皮质神经元的活动。这个大脑区域与奖励和判断有关，并且在可卡因成瘾和艾滋病中都会受到损害。我们认为，反复接触可卡因会加剧由 HIV 蛋白 Tat 引起的内侧前额叶皮层神经元活动的变化。这项研究的结果将帮助我们验证可卡因滥用和艾滋病毒感染的共同目标，这对于开发针对可卡因滥用和艾滋病毒相关大脑/行为缺陷的更有效治疗方法非常重要。