K channel, NLRP3 inflammasome and Meth exacerbation of HAND

K 通道、NLRP3 炎性体和 Meth 加剧 HAND

基本信息

批准号：
10017025
负责人：
HUANGUI Hank XIONG
金额：
$ 41.15万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017025
关键词：
Affect Anti-Retroviral Agents Applications Grants Behavior Behavioral Biological Biological Assay Biological Markers Biology Brain Cell physiology Cells Characteristics Chemosensitization Dementia Development Disease Disease Outcome Drug abuse Electrophysiology (science)Exposure to Funding Goals HIV HIV Envelope Protein gp120 HIV-1 HIV-associated neurocognitive disorder Human Impaired cognition Infection Inflammasome Inflammation Inflammatory Inflammatory Response Investigation Laboratory Animal Models Lamivudine Lead Learning Link Lipopolysaccharides Medical center Membrane Memory Methamphetamine Microglia Molecular Molecular Target Morbidity - disease rate Nebraska Neurocognitive Deficit Neuronal Dysfunction Neuronal Injury Neurons Neurotoxins Outcome Patch-Clamp Techniques Pathogenesis Pathology Pattern Pharmaceutical Preparations Physiological Physiology Play Polyethylene Terephthalates Potassium Channel Production Proteins Rattus Rest Role Severities Signal Transduction Stimulus Synaptic plasticity Testing Time Universities Up-Regulation Viral Viral Proteins Virion Virus Virus Diseases Virus Replication Voltage-Gated Potassium Channel Western Blotting antiretroviral therapy base cell motility cell type comorbidity cytokine drug of abuse experience experimental study humanized mouse immune activation inhibitor/antagonist interest macrophage migration neuroinflammation neurotoxic neurotoxicity patch clamp potential biomarker receptor response specific biomarkers targeted treatment therapeutic development voltage water maze

项目摘要

Abstract Despite effective combination antiretroviral therapy (cART), virus persists in brain at low levels often in a latent or restricted manner. Immune activation and inflammation continues and is linked to viral and cellular neurotoxic proteins and co-morbid infections along with drugs of abuse. The severity of inflammation that occurs during cART is well known to be worsened by methamphetamine (Meth). The mechanisms that underlie such disease outcomes remain poorly understood. Complicating the ability to decipher mechanisms is that antiretroviral drugs (ARVs) may themselves affect inflammatory responses and elicit neurotoxicity during long- term usage. Thus, HIV, drugs of abuse and ARVs are believed to orchestrate changes in the brain’s microenvironment leading to microglia (MG) activation and consequent inflammatory activities. These, over time, affect the development of HIV-associated neurocognitive disorders (HAND). To date, there is considerable interest in strategies that regulate MG activation and resultant inflammation. Thus, investigations on development of specific biomarkers to judge the severity of inflammation and identification of specific targets to control MG activation and inflammation are of immediate importance. MG express outward delayed rectifier Kv1.3, with a direct tie into functional marker of MG activation and NLRP3 inflammasome is involved in HIV-induced MG activation. However, there is very limited information available on how Kv1.3 can be “best” utilized as a biomarker for Meth potentiation of HIV-associated MG NLRP3 inflammasome activation. To this end, we seek funds to develop Kv1.3 as a potential biomarker and to evaluate its potential as an intersecting target for HIV, Meth and ARVs in laboratory and animal models. In specific aim 1, we will determine and characterize the role of Kv1.3 in Meth- and ARV-induced potentiation of MG activation, migration, production of neurotoxins and neurotoxic activity via NLRP3 activation. In specific aim 2, we will investigate the relationships between Kv1.3-associated MG NLRP3 activation and HIV-associated neuronal injury and behavioral deficits in infected humanized mice. We theorize that Kv1.3 channels can be harnessed as physiological biomarkers for inflammation and neurotoxicity seen during HAND. This rests in the fact that such channels closely regulate MG activation, migration and production of pro-inflammatory substances. Overall, these studies, if successful, may have the potential to develop a biomarker for judging the severity of HIV-, Meth- and ARV-associated neuroinflammation and to identify a potential intersecting target for the development of therapeutic strategies.

抽象的尽管有有效的联合抗逆转录病毒疗法（cART），病毒仍然以低水平持续存在于大脑中，并且通常处于潜伏状态。免疫激活和炎症持续存在，并与病毒和细胞有关。神经毒性蛋白质和合并症感染以及滥用药物引起的炎症的严重程度。众所周知，cART 期间发生的这种情况会因甲基苯丙胺 (Meth) 的作用而加剧。这种疾病的结果仍然知之甚少，使破译机制的能力变得更加复杂。抗逆转录病毒药物（ARV）本身可能会影响炎症反应并在长期治疗期间引起神经毒性。因此，艾滋病毒、滥用药物和抗逆转录病毒药物被认为可以协调大脑的变化。微环境导致小胶质细胞（MG）激活和随后的炎症活动。迄今为止，存在影响艾滋病毒相关神经认知障碍（HAND）的发展。对调节 MG 激活和由此产生的炎症的策略非常感兴趣。开发特异性生物标志物来判断炎症的严重程度和识别特异性控制 MG 激活和炎症的目标具有直接重要性。整流子 Kv1.3，与 MG 激活的功能标记直接相关，NLRP3 炎性体参与然而，关于 Kv1.3 如何成为“最佳”的信息非常有限。用作 HIV 相关 MG NLRP3 炎性体激活的 Meth 增强的生物标志物。最后，我们寻求资金来开发 Kv1.3 作为潜在的生物标志物，并评估其作为交叉的潜力在具体目标 1 中，我们将确定并确定实验室和动物模型中艾滋病毒、冰毒和抗逆转录病毒药物的目标。描述 Kv1.3 在 Meth 和 ARV 诱导的 MG 激活、迁移、产生增强作用中的作用在具体目标 2 中，我们将研究通过 NLRP3 激活产生的神经毒素和神经毒性活性。 Kv1.3 相关 MG NLRP3 激活与 HIV 相关神经元损伤和行为缺陷之间的关系我们推测 Kv1.3 通道可以用作生理生物标志物 HAND 过程中出现的炎症和神经毒性是因为这些通道密切调节。总的来说，如果这些研究成功，MG 的激活、迁移和促炎物质的产生。可能有潜力开发一种生物标志物来判断艾滋病毒、冰毒和抗逆转录病毒相关疾病的严重程度神经炎症并确定开发治疗策略的潜在交叉目标。