Electrophysiological mechanisms of HIV-mediated neuropathogenesis

HIV介导的神经病变的电生理机制

• 批准号: 8697161
• 负责人: XIU-TI HU
• 金额: $ 47.94万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697161
• 关键词: Address; Adolescent; Age; Aging; Aging-Related Process; Animal Model; Automobile Driving; Biochemical; Brain; Cells; Clinical Research; Cognition; Cognitive; Combined Modality Therapy; Corpus striatum structure; Data; Diagnosis; Diltiazem; Disease; Dopamine D1 Receptor; Dorsal; Functional disorder; Future; Genes; Genetic Transcription; Glutamates; HIV; HIV Infections; HIV-1; In Vitro; Injury; Ion Channel; L-Type Calcium Channels; Life; Ligands; Medial; Mediating; Memantine; Membrane; Modeling; Molecular; Motor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neurocognitive; Neuronal Injury; Neurons; Neuropathogenesis; Optics; Pathway interactions; Patients; Physiological; Physiology; Play; Population; Prefrontal Cortex; Proteins; Publishing; Pyramidal Cells; Rattus; Research; Risk Factors; Role; Severity of illness; Signal Transduction; Slice; Staging; Stimulus; Testing; Therapeutic Intervention; Trans-Activators; Transgenic Organisms; age related; aged; aging brain; antiretroviral therapy; channel blockers; excitotoxicity; fluorescence imaging; hippocampal pyramidal neuron; human CREB1 protein; in vivo; innovation; neuropathology; novel; novel therapeutics; 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）：尽管抗逆转录病毒疗法，美国约有50％的HIV+患者被诊断出患有HIV相关的神经认知疾病（HAND）。艾滋病毒改变了认知和心理运动活性的两个关键调节剂，内侧前额叶皮层（MPFC）和尾状甲状腺肿（CPU; a.k.A.背纹状体）。过量的Ca2+流入（部分通过NMDA受体，NMDAR）在神经元兴奋性毒性中至关重要，但是HIV神经病发生的机制并不完全清楚。我们已发表的PILOT数据指出了HIV介导的神经元超过性的附加机制，该机制涉及电压门控L型Ca2+通道，而与NMDAR无关。我们表明，HIV-1转录（TAT）通过上调MPFC锥体神经元中的L通道来增加Ca2+流入，从而使这些细胞更容易受到敏感，并且容易发生过度效能。 TAT还增强了NMDAR和L通道之间的相互作用，神经元与使用HIV-1转基因（TG）大鼠的老化或建模相似的过度激发。这些发现共同指出了一种独特的机制，艾滋病毒引起过多的神经兴趣。鉴于L通道阻滞剂和单独的NMDAR拮抗剂都无法在晚期治疗手，因此了解HIV和L通道之间的复杂相互作用都可以为手提供新颖的治疗策略。我们的中心假设是，大脑的艾滋病毒感染使MPFC锥体神经元和CPU培养基神经元（MSN）更容易受到刺激，并且通过过度激活L频道刺激刺激。而L通道和NMDAR阻滞剂的合并处理将改善MPFC/CPU神经病理生理学，而在青少年中，比在较老的大脑中更有效。我们将使用综合的电生理，光学/荧光成像和免疫/生化方法通过三个目标检验这一假设。在AIM 1中，我们将定义艾滋病毒介导L通道过度激活的细胞/分子机制，从而在青少年TG大鼠的MPFC/CPU中介导L通道过度激活。我们预计，受感染细胞释放的HIV-1蛋白通过引进的多巴胺D1受体（D1R）部分介导L通道过度激活，并将揭示介导TAT对L通道影响的TAT域。在AIM 2中，我们将评估NMDAR和L通道之间的相互作用，以介导神经元超过性。我们假设NMDA诱发的Ca2+信号被LVA-L通道过度扩增，并通过LVA-L通道传递到最终控制发射的其他离子通道。在AIM 3中，我们将确定年龄（一个重要的手动风险因素）在L通道过度激活和MPFC/CPU神经病理生理学中与老年大鼠相关的加重。我们假设MPFC/CPU神经病理生理学在老龄化TG大鼠中比青少年TG大鼠（和衰老的非TG大鼠）更为严重。最近，我们预计L通道/NMDAR阻滞剂的联合治疗将减少/改善HIV介导的神经元超过性。总的来说，我们的研究将在HIV介导的神经病发生中建立一种新的范式，并确定用于未来治疗性干预艾滋病毒介导的神经病理学的新靶标。