Microglial ion channels and HIV-1-associated dementia

小胶质细胞离子通道和 HIV-1 相关痴呆

基本信息

批准号：
8512830
负责人：
HUANGUI Hank XIONG
金额：
$ 35.83万
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：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512830
关键词：
AIDS neuropathy Animal Model Applications Grants Attention Attenuated Behavioral Biological Blood - brain barrier anatomy Brain Brain Injuries CCR5 gene CXCR4 gene Cessation of life Characteristics Chemicals Cyclic AMP-Dependent Protein Kinases Dementia Disease Excitatory Amino Acids Exhibits Exposure to FDA approved Funding Goals HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Immunocompetent Impaired cognition Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Response Injury Intervention Ion Channel Kir2.1 channel Laboratory Animal Models Link MAP Kinase Gene MAPK14 gene Mediating Microglia Modeling Molecular Mus Neurocognitive Neurodegenerative Disorders Neuronal Dysfunction Neuronal Injury Neurons Neurotoxins Nitric Oxide Pathogenesis Pattern Phagocytes Pharmaceutical Preparations Play Potassium Process Production Reactive Oxygen Species Research Rest Role Severe Combined Immunodeficiency Signal Pathway Signal Transduction Slice Stimulus System Techniques Testing Therapeutic Up-Regulation Vesicular stomatitis Indiana virus Viral Proteins Virus base cell type channel blockers chemokine combat cytokine design human disease in vivo injured interest killings migration mouse model nervous system disorder neuroprotection neurotoxic neurotoxicity prevent response therapeutic development tissue culture voltage

项目摘要

DESCRIPTION (provided by applicant): Microglia (MG) are resident immunocompetent phagocytic cells strongly linked to the pathogenesis of HIV-1- associated neurocognitive disorders (HAND). HIV-1 brain infection triggers MG activation and neuroinflammatory responses reflective of the production of pro-inflammatory factors that elicit neuronal dysfunction and death. To date, there is considerable interest in strategies that modulate MG-associated inflammation and research on identification of specific target(s) in controlling MG neurotoxic activities is imperative. It is well-known that MG express a variety of ion channels and the voltage-gated K+ (Kv) channels have recently gained attention as promising targets for therapy of neurological disorders. Nonetheless, there is very limited information available on how Kv channels can be "best" utilized for therapeutic benefit. To this end, we seek funds to study the role of Kv channels, specifically the Kv1.3, in HIV-1-induced MG activation, migration, production of neurotoxins, resultant neurotoxicity and consequent HAND pathogenesis. Electrophysiological, pharmacological, molecular and immunocyto(histo)chemical techniques will examine the role of Kv1.3 in regulating MG function in laboratory and animal models of human disease. In specific aim 1 we will determine involvement of Kv1.3 channels in HIV-1gp120- and virus-induced MG activation, migration, resultant neurotoxic activity and their potential signaling pathways. In specific aim 2 we will assess the role of Kv1.3 in MG-induced neuronal dysfunction/injury and cognitive impairment in a murine model of neuroAIDS and explore therapeutic potential of Kv channel antagonists in this animal model. Overall, these studies focus on not only understanding the role(s) that Kv1.3 might play in MG-associated neurotoxic activity and HAND pathogenesis, but also identifying potential target(s) for the development of therapeutic strategies. If successful, these studies will provide a proper roadmap for expected efficacy of Kv channel antagonists in ameliorating HIV-1-induced brain injury.

描述（由申请人提供）：小胶质细胞（MG）是常驻免疫活性吞噬细胞，与HIV-1相关神经认知障碍（HAND）的发病机制密切相关。 HIV-1脑部感染触发 MG 激活和神经炎症反应，反映促炎因子的产生，从而引起神经元功能障碍和死亡。迄今为止，人们对调节 MG 相关炎症的策略非常感兴趣，并且必须研究识别控制 MG 神经毒性活动的特定靶点。众所周知，MG 表达多种离子通道，电压门控 K+ (Kv) 通道最近作为治疗神经系统疾病的有希望的靶点而受到关注。尽管如此，关于如何“最好”利用 Kv 通道以获得治疗效果的信息非常有限。为此，我们寻求资金来研究 Kv 通道（特别是 Kv1.3）在 HIV-1 诱导的 MG 激活、迁移、神经毒素产生、由此产生的神经毒性和随后的 HAND 发病机制中的作用。电生理学、药理学、分子和免疫细胞（组织）化学技术将研究 Kv1.3 在人类疾病的实验室和动物模型中调节 MG 功能的作用。在具体目标 1 中，我们将确定 Kv1.3 通道在 HIV-1gp120 和病毒诱导的 MG 激活、迁移、由此产生的神经毒性活性及其潜在信号传导通路中的参与。在具体目标 2 中，我们将评估 Kv1.3 在神经艾滋病小鼠模型中 MG 诱导的神经元功能障碍/损伤和认知障碍中的作用，并探索 Kv 通道拮抗剂在该动物模型中的治疗潜力。总体而言，这些研究不仅侧重于了解 Kv1.3 在 MG 相关神经毒性活动和 HAND 发病机制中可能发挥的作用，而且还致力于确定开发治疗策略的潜在靶点。如果成功，这些研究将为 Kv 通道拮抗剂改善 HIV-1 引起的脑损伤的预期功效提供适当的路线图。