Macrophages, NR2B-containing NMDA Receptors and HIV Dementia

巨噬细胞、含 NR2B 的 NMDA 受体与 HIV 痴呆

基本信息

批准号：
8214594
负责人：
HUANGUI Hank XIONG
金额：
$ 36.38万
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：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214594
关键词：
Acquired Immunodeficiency Syndrome Affect Animal Model Animals Antibodies Apoptotic Astrocytosis Basal Ganglia Bathing Behavior Biological Biological Assay Blood Brain Brain Injuries Brain region CD40 Ligand Cell Death Cell Death Signaling Process Cell Survival Cell model Cells Cessation of life Chronic Coculture Techniques Conditioned Culture Media Control Animal Cues Data Dementia Development Disease Dyes Electrodes Exhibits Failure Figs - dietary Foundations Frequencies Functional disorder Funding Genes Giant Cells Glutamates Goals HIV HIV encephalitis HIV-1 Health Highly Active Antiretroviral Therapy Hippocampus (Brain)Human Human immunodeficiency virus test Immune Impaired cognition Impairment Individual Indoles Infection Inflammatory Interleukin-1 Knock-out Laboratories Laboratory Animal Models Learning Link Location Long-Term Potentiation MK801 Macrophage Activation Mediating Memory Microglia Microtubule-Associated Protein 2 Modeling Mononuclear Morphology Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist NR1 gene NR2B NMDA receptor Nerve Degeneration Neurocognitive Neurodegenerative Disorders Neuroglia Neuronal Dysfunction Neuronal Injury Neurons Neuropathogenesis Neurotoxins Nodule Oocytes Pathogenesis Pathway interactions Patients Perfusion Phagocytes Physiology Play Prevention Property Propidium Diiodide Proteins Proteomics Protocols documentation Radial Rattus Relative (related person)Role SCID Mice Scheme Signal Pathway Signal Transduction Signal Transduction Pathway Slice Small Interfering RNA Staining method Stains Synapses Synaptic Transmission Synaptic plasticity System Techniques Testing Therapeutic Time Tissues Toxin Viral Virus Virus Diseases Virus Replication Water Western Blotting Work Xenopus oocyte arm aspartate receptor base behavior test biological systems caspase-3 channel blockers chemokine cognitive change cognitive function cytokine excitotoxicity human disease ifenprodil immune activation in vivo insight knock-down macrophage memory process monocyte mouse model neuronal survival neuropathology neurotoxic neurotropic postsynaptic prevent protective effect receptor release factor research study response therapeutic target voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Synaptic N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), composed, in large part, of NR2A-containing NMDARs (NR2ARs), promote cell survival, whereas extrasynaptic NMDARs, NR2B-containing NMDARs (NR2BRs), induce cell death. It is known that a host of macrophage inflammatory and viral products engage NMDARs, but there is very limited information available on how these receptors can be "best" utilized for optimal therapeutic benefit. To this end we seek funds to assess the role of HIV-1-infected and immune competent mononuclear phagocytes (MPs, brain perivascular macrophages and microglia) to affect extrasynaptic NR2BRs. MPs are the natural virus target cells and the key to neuronal dysfunction in HIV-1- associated neurocognitive disorders (HAND). Immunocytochemical, pharmacological and electrophysiological techniques will examine the role of extrasynaptic NR2BRs in HIV-1 infected MP-induced neuronal dysfunction and resultant cognitive impairment in laboratory and animal models of human disease. First, we will examine direct activation of NR2BRs by HIV-1 infected MP and resultant neurotoxic activity. Second, we will investigate the role of NR2BRs in HIV-1 infected MP-induced alteration of synaptic transmission and plasticity. Third, we will study whether HIV-1 infected MP-induced, NR2BR-mediated alteration of cellular and synaptic physiology contributes to HAND, and to explore potential protective effects of NR2BR antagonists in a relevant murine model of HIV disease. Overall, these studies are focused toward not only understanding the role that the subtype and location of NMDARs might play in HAND, but also on developing more realistic means to harness these pathways for therapeutic benefit. If successful, these studies will provide a proper roadmap for expected efficacy of NMDAR antagonists in ameliorating brain injury. PUBLIC HEALTH RELEVANCE: Synaptic N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), composed, in large part, of NR2A-containing NMDARs (NR2ARs), promote cell survival, whereas extrasynaptic NMDARs, NR2B-containing NMDARs (NR2BRs), induce cell death. This proposal investigates how HIV-1-infected mononuclear phagocytes (brain macrophages and microglia) activate neuronal extrasynaptic NR2BRs, leading to neuronal damage and ultimately neurocognitive dysfunction. By completion of the proposed studies we will not only provide new insights into the mechanisms underlying the neuropathogenesis of HIV-1 infection, but also furnish new target(s) for the development of potential therapies in the prevention and treatment of HIV-1 disease.

描述（由申请人提供）：突触 N-甲基-D-天冬氨酸 (NMDA) 受体 (NMDAR) 大部分由含有 NR2A 的 NMDAR (NR2AR) 组成，可促进细胞存活，而突触外 NMDAR 则含有 NR2B NMDAR (NR2BR) 诱导细胞死亡。众所周知，许多巨噬细胞炎症和病毒产物都会与 NMDAR 结合，但关于如何“最好”地利用这些受体以获得最佳治疗效果的信息非常有限。为此，我们寻求资金来评估感染 HIV-1 且具有免疫能力的单核吞噬细胞（MP、脑血管周围巨噬细胞和小胶质细胞）对突触外 NR2BR 的影响。 MP 是天然病毒靶细胞，也是 HIV-1 相关神经认知障碍 (HAND) 神经元功能障碍的关键。免疫细胞化学、药理学和电生理学技术将在人类疾病的实验室和动物模型中研究突触外 NR2BR 在 HIV-1 感染 MP 诱导的神经元功能障碍和由此产生的认知障碍中的作用。首先，我们将检查 HIV-1 感染的 MP 对 NR2BR 的直接激活以及由此产生的神经毒性活性。其次，我们将研究 NR2BR 在 HIV-1 感染 MP 诱导的突触传递和可塑性改变中的作用。第三，我们将研究HIV-1感染的MP诱导的、NR2BR介导的细胞和突触生理学改变是否有助于HAND，并探索NR2BR拮抗剂在相关HIV疾病小鼠模型中的潜在保护作用。总体而言，这些研究不仅致力于了解 NMDAR 的亚型和位置在 HAND 中可能发挥的作用，而且致力于开发更现实的方法来利用这些途径获得治疗益处。如果成功，这些研究将为 NMDAR 拮抗剂改善脑损伤的预期功效提供适当的路线图。公共卫生相关性：突触 N-甲基-D-天冬氨酸 (NMDA) 受体 (NMDAR) 大部分由含有 NR2A 的 NMDAR (NR2AR) 组成，可促进细胞存活，而突触外 NMDAR、含有 NR2B 的 NMDAR (NR2BR) ），诱导细胞死亡。该提案研究了 HIV-1 感染的单核吞噬细胞（脑巨噬细胞和小胶质细胞）如何激活神经元突触外 NR2BR，导致神经元损伤并最终导致神经认知功能障碍。通过完成拟议的研究，我们不仅将为 HIV-1 感染的神经发病机制提供新的见解，而且还将为开发预防和治疗 HIV-1 疾病的潜在疗法提供新的目标。