Electrophysiological mechanisms of HIV-mediated neuropathogenesis

HIV介导的神经病变的电生理机制

• 批准号: 9296193
• 负责人: XIU-TI HU
• 金额: $ 56.76万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296193
• 关键词: Address; Adolescent; Age; Aging; Aging-Related Process; Animal Model; Automobile Driving; Biochemical; Brain; Calcium Channel; Cells; Clinical Research; Cognition; Cognitive; Combined Modality Therapy; Corpus striatum structure; Data; Diagnosis; Diltiazem; Dopamine D1 Receptor; Dorsal; Electrophysiology (science); Functional disorder; Future; Gene Expression; Genetic Transcription; Glutamates; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; In Vitro; Injury; Ion Channel; Ligands; Medial; Mediating; Memantine; Membrane; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuronal Injury; Neurons; Neuropathogenesis; Optics; Pathway interactions; Patients; Permeability; Physiology; Play; Population; Prefrontal Cortex; Proteins; Publishing; Pyramidal Cells; Rattus; Research; Risk Factors; Role; Severity of illness; Signal Transduction; Slice; Stimulus; Testing; Therapeutic Intervention; Toxic effect; Trans-Activators; Transgenic Organisms; age related; aged; aging brain; antiretroviral therapy; channel blockers; excitotoxicity; fluorescence imaging; hippocampal pyramidal neuron; in vivo; innovation; motor deficit; neuropathology; novel; novel therapeutics; overexpression; prevent; psychosocial; public health relevance; putamen; success; voltage

DESCRIPTION (provided by applicant): Despite antiretroviral therapy, approximately 50% of HIV+ patients in the USA are diagnosed with HIV-associated neurocognitive disorders (HAND). HIV alters two key regulators of cognition and psychomotor activity, the medial prefrontal cortex (mPFC) and caudate-putamen (CPu; a.k.a. dorsal striatum). Excessive Ca2+ influx (partly via NMDA receptor, NMDAR) is critical in neuronal excitotoxicity, but the mechanisms underlying HIV neuropathogenesis are not entirely clear. Our published and pilot data point to an additional mechanism in HIV-mediated neuronal hyper-excitability which involves the voltage-gated L-type Ca2+ channel, independent of NMDAR. We showed that HIV-1 transactivator of transcription (Tat) increases Ca2+ influx by upregulating L-channels in mPFC pyramidal neurons, rendering these cells more susceptible and vulnerable to hyper-excitability. Tat also potentiates the interaction between NMDAR and L-channel, and neurons showed similar over-excitation as aged or modeled using HIV-1 transgenic (Tg) rats. Together, these findings point to a unique mechanism by which HIV induces excessive neuroexcitation. Given that neither an L-channel blocker nor a NMDAR antagonist alone was able to treat HAND at late stage, understanding the intricate interplay between HIV and the L-channels may provide novel therapeutic strategies for HAND. Our central hypothesis is that HIV infection of the brain renders mPFC pyramidal neurons and CPu medium spiny neurons (MSNs) more susceptible and vulnerable to excitatory stimuli via over-activating the L-channels; and that combined treatments of an L-channel and NMDAR blocker will ameliorate the mPFC/CPu neuropathophysiology, more effectively in adolescent than in older brain. We will test this hypothesis via three aims using integrated electro- physiological, optic/fluorescence imaging and immuno/biochemical approaches. In Aim 1 we will define the cellular/molecular mechanism(s) by which HIV mediates L-channel over-activation and consequently neuronal hyper-excitation in the mPFC/CPu of adolescent Tg rats. We expect that HIV-1 proteins released by infected cells mediate L-channel over-activation in part via engaging dopamine D1 receptor (D1R), and will reveal the domain of Tat that mediates the Tat effects on L-channels. In Aim 2 we will evaluate the interplay between NMDAR and L-channel in mediating neuronal hyper-excitability. We hypothesize that NMDA-evoked Ca2+ signal is over-amplified and relayed by LVA-L channels to other ion channels that ultimately control firing. In Aim 3 we will ascertain age (a significant risk factor for HAND)-associated exacerbation in L-channel over-activation and mPFC/CPu neuropathophysiology in older Tg rats. We hypothesize that mPFC/CPu neuropathophysiology will be more severe in aging Tg rats than in adolescent Tg rats (and aging non-Tg rats). Lately, we expect that combined treatments of L-channel/NMDAR blockers will diminish/ameliorate HIV-mediated neuronal hyper-excitability. Collectively, our studies will establish a novel paradigm in HIV-mediated neuropathogenesis and identify novel targets for future therapeutic intervention for HIV-mediated neuropathology.

描述（由申请人提供）：尽管进行了抗逆转录病毒治疗，美国大约 50% 的 HIV+ 患者仍被诊断患有 HIV 相关神经认知障碍 (HAND)。 HIV 改变认知和精神运动活动的两个关键调节因子，即内侧前额皮质 (mPFC) 和尾壳核 (CPu；又名背侧纹状体)。过多的 Ca2+ 流入（部分通过 NMDA 受体，NMDAR）对于神经元兴奋性毒性至关重要，但 HIV 神经发病机制的机制尚不完全清楚。我们发表的试验数据指出了 HIV 介导的神经元过度兴奋的另一种机制，其中涉及电压门控 L 型 Ca2+ 通道，独立于 NMDAR。我们发现 HIV-1 转录反式激活因子 (Tat) 通过上调 mPFC 锥体神经元中的 L 通道来增加 Ca2+ 流入，使这些细胞更容易过度兴奋。 Tat 还增强了 NMDAR 和 L 通道之间的相互作用，神经元表现出与衰老或使用 HIV-1 转基因 (Tg) 大鼠建模​​相似的过度兴奋。总之，这些发现指出了艾滋病毒诱导过度神经兴奋的独特机制。鉴于单独使用 L 通道阻滞剂或 NMDAR 拮抗剂都无法在晚期治疗 HAND，了解 HIV 和 L 通道之间复杂的相互作用可能为 HAND 提供新的治疗策略。我们的中心假设是，大脑的 HIV 感染使 mPFC 锥体神经元和 CPu 中型多棘神经元 (MSN) 更容易通过过度激活 L 通道而受到兴奋性刺激； L 通道和 NMDAR 阻滞剂的联合治疗将改善 mPFC/CPu 神经病理生理学，在青少年大脑中比在老年大脑中更有效。我们将使用综合电生理、光学/荧光成像和免疫/生化方法通过三个目标来检验这一假设。在目标 1 中，我们将定义 HIV 介导 L 通道过度激活以及因此导致青少年 Tg 大鼠 mPFC/CPu 神经元过度兴奋的细胞/分子机制。我们预计，受感染细胞释放的 HIV-1 蛋白部分通过接合多巴胺 D1 受体 (D1R) 介导 L 通道过度激活，并将揭示介导 Tat 对 L 通道影响的 Tat 结构域。在目标 2 中，我们将评估 NMDAR 和 L 通道在介导神经元过度兴奋方面的相互作用。我们假设 NMDA 诱发的 Ca2+ 信号被过度放大并通过 LVA-L 通道传递到最终控制放电的其他离子通道。在目标 3 中，我们将确定老年 Tg 大鼠中与年龄（HAND 的重要危险因素）相关的 L 通道过度激活和 mPFC/CPu 神经病理生理学恶化。我们假设衰老 Tg 大鼠的 mPFC/CPu 神经病理生理学比青少年 Tg 大鼠（和衰老非 Tg 大鼠）更严重。最近，我们预计 L 通道/NMDAR 阻滞剂的联合治疗将减少/改善 HIV 介导的神经元过度兴奋。总的来说，我们的研究将为 HIV 介导的神经病理学建立一个新的范例，并确定未来 HIV 介导的神经病理学治疗干预的新靶点。