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：
10663307
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663307
关键词：
Affect Animal Model 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 Kv1.3 potassium channel Laboratories Lamivudine Learning Link Lipopolysaccharides Macrophage 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 cell motility cell type comorbidity cytokine drug of abuse experience experimental study humanized mouse immune activation inhibitor interest migration neuroinflammation neurotoxic neurotoxicity patch clamp potential biomarker receptor response screening specific biomarkers theories therapeutic development translational potential 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.

抽象的尽管有效组合抗逆转录病毒疗法（CART），但病毒通常在低水平中持续存在或限制方式。免疫激活和感染继续，与病毒和细胞有关神经毒性蛋白和合并感染以及滥用药物。感染的严重程度众所周知，甲基苯丙胺（甲基苯丙胺）忘记了货车。基础的机制这样的疾病结果仍然很糟糕。使解密机制的能力复杂化的是抗逆转录病毒药物（ARV）本身可能会影响炎症反应，并在长期产生神经毒性使用期限。艾滋病毒，据信，虐待和ARV的药物会策划大脑的变化微环境导致小胶质细胞（MG）激活和随之而来的炎症活性。这些，结束时间，影响与HIV相关的神经认知障碍的发展（手）。迄今为止，有对调节MG激活和产生投资的策略的极大兴趣。那，调查关于开发特定的生物标志物来判断炎症的严重程度和特定的识别控制MG激活和炎症的目标至关重要。 MG Express向外延迟整流器kv1.3，直接绑定了MG激活和NLRP3炎症体的功能标记 HIV诱导的MG激活。但是，关于KV1.3如何“最好”的信息非常有限用作与HIV相关的MG NLRP3炎性体激活的甲基甲基标记物的生物标志物。对此最后，我们寻求资金开发KV1.3作为潜在的生物标志物，并评估其作为相交的潜力实验室和动物模型中的艾滋病毒，甲基苯丙胺和ARV的靶标。在特定目标1中，我们将确定和表征KV1.3在MED和ARV诱导的MG激活，迁移，生产中的作用神经毒素和神经毒性通过NLRP3激活。在特定目标2中，我们将研究关系在KV1.3相关的MG NLRP3激活与HIV相关的神经元损伤和行为缺陷之间被感染的人源性小鼠。我们认为KV1.3频道可以作为物理生物标志物的物理生物标志物的在手中看到的炎症和神经毒性。这是因为这种渠道密切调节的事实促炎性物质的MG激活，迁移和生产。总的来说，如果成功的话，这些研究可能有可能开发生物标志物来判断HIV，METH和ARV相关的严重程度神经炎症并确定一种潜在的与治疗策略发展的相交靶标。