AIDS-Related Neurotoxicity and Novel NMDAR Antagonists

艾滋病相关神经毒性和新型 NMDAR 拮抗剂

基本信息

批准号：
7289794
负责人：
STUART A LIPTON
金额：
$ 46.37万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-02-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7289794
关键词：
AIDS Dementia Complex AIDS clinical trial group Accounting Acquired Immunodeficiency Syndrome Adamantane Adult Adverse effects Affect Affinity Alzheimer&apos s Disease Animals Apoptosis Area Astrocytes Biological Models Brain Breeding Capsid Proteins Cell Death Charge Chemicals Class Clinical Research Clinical Trials Cognitive Collaborations Complement Condition Cysteine D Aspartate Data Analyses Development Down-Regulation Electrons Eye Family Funding Genetic Genetic screening method Glutamate Receptor Grant HIV HIV Envelope Protein gp120 HIV-1 Histologic Human Hyperactive behavior Hypotension In Vitro Incubated Infection Injection of therapeutic agent Injury Intervention Ion Channel Knock-out Knockout Mice Knowledge Laboratories Lead Left Letters Literature Magnetic Resonance Magnetic Resonance Spectroscopy Malignant Neoplasms Measures Mediating Memantine Microglia Microscopy Mind Modeling Molecular Molecular Genetics Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 gene Nature Nebraska Neuraxis Neurologic Neurologic Manifestations Neuronal Injury Neurons Neuroprotective Agents Neuropsychological Tests Nitrates Nitric Oxide Organism Pharmaceutical Preparations Phase Phase II Clinical Trials Physiological Play Prevention Principal Investigator Protein Overexpression Purpose Rate Research Personnel Retina Retinal Retinal Ganglion Cells Rodent Rodent Model Role SCID Mice Safety Score Signal Transduction Site Specificity Synapses Synaptic Transmission Synaptic plasticity Testing Thinking Toxic effect Toxin Transgenes Transgenic Mice Transgenic Organisms United States Food and Drug Administration United States National Institutes of Health Universities Work adduct base cell injury clinical efficacy drug development drug testing genetic manipulation human NR1 protein improved in vivo macrophage monocyte mouse model neuronal survival neuroprotection neurotoxicity neurotransmission nitrate novel pre-clinical preclinical study prevent programs receptor receptor function research study voltage

项目摘要

DESCRIPTION (provided by applicant): The neurological manifestations of HIV-1 affect approximately one-quarter of adults with AIDS. In addition to super-infections with opportunistic organisms and malignancy, damage in the CNS in AIDS appears to be most closely associated with toxins released by brain microglia/macrophages that have been infected by HIV or stimulated by the viral coat protein, gp!20. Neurons themselves are most likely not infected, but undergo dendritic and synaptic injury and may succumb to apoptosis. At least part of this damage is accounted for by macrophage and possibly astrocyte toxic factors leading to overexcitation of glutamate receptors, especially of the W-methyl-D-aspartate subtype (NMDARs), as shown previously by this grant. Also, this grant helped develop the first clinically-tolerated NMDAR antagonist, Memantine, which led to phase 2 clinical trials for HIV-associated dementia. Here we propose to develop a class of NMDAR antagonists that are superior to Memantine. These new drugs are termed NO-Memantines and are being developed to prevent neuronal injury engendered by gp!20 in the following model systems: (a) in vitro in rodent cerebrocortical cultures, (b) in vivo in a rodent retinal model using intravitreal injection of gp!20 into the eye, and (c) in vivo in a gp120- transgenic mouse model. Additionally, our group has cloned and characterized a new family of NMDAR subunits, called NR3, which when combined with conventional NR1 and NR2 subunits, lead to decreased NMDAR activity, in a sense mimicking the effect of Memantine. Here we propose to study the effect of NR3 on gp!20-induced neuronal damage in similar models to those used for drug testing. We have produced NR3 knockout and transgenic mice to breed with gp!20-transgenic mice for this purpose. The resulting mice will be analyzed histologically by confocal/deconvolution microscopy and behaviorally for evidence of amelioration of gp!20-induced damage. This molecular approach using NR3 subunits will be used to validate the effect of drugs that inhibit excessive NMDAR activity to protect neurons from gp120-induced damage. It is anticipated that these preclinical studies investigating the role of the NMDAR in neuronal cell injury may lead to new treatments for the neurological manifestations of AIDS.

描述（由申请人提供）：HIV-1的神经系统表现影响大约四分之一的成年人使用艾滋病。除了与机会主义生物体和恶性肿瘤的超级感染外，艾滋病中CNS的损害似乎与脑部小胶质细胞/巨噬细胞释放的毒素最紧密相关，这些毒素已被HIV感染或被病毒外套蛋白刺激的毒素GP！20。神经元本身很可能没有感染，但是会遭受树突状和突触损伤，并可能屈服于凋亡。巨噬细胞和可能是星形胶质细胞毒性因子，导致谷氨酸受体过度激发，特别是W-甲基-D-天冬氨酸亚型（NMDARS）的至少部分损害，可能是由星形胶质细胞的。此外，该赠款有助于开发了第一个临床上耐受性的NMDAR拮抗剂美体动物，这导致了与HIV相关痴呆症的第二阶段临床试验。在这里，我们建议开发一类NMDAR拮抗剂，这些拮抗剂优于美灵。这些新药物被称为无象征性，正在开发以防止GP！20在以下模型系统中引起的神经元损伤：（a）在啮齿动物脑皮层培养物中体外，（b）在啮齿动物的视网膜模型中使用GP！20的啮齿类视网膜模型中的啮齿动物视网膜模型中的viv！20 in Eye和（c）In vivo In vivo In vivo In vivo in the gp120- transfec120- transic infen fen gp120- trans-incic incic incic incic incic inciC120- c120--此外，我们的小组已经克隆并表征了一个新的NMDAR亚基家族，称为NR3，该系列与常规的NR1和NR2亚基相结合，从而导致NMDAR活性降低，从而模仿了美容效果。在这里，我们建议研究NR3对GP！20诱导的神经元损伤的影响，与用于药物测试的模型相似。为此，我们生产了NR3敲除和转基因小鼠，用GP！20-转基因小鼠繁殖。将通过共焦/反卷积显微镜在组织学上分析所得小鼠，并在行为上以改善GP！20诱导的损伤的证据。使用NR3亚基的这种分子方法将用于验证抑制过度NMDAR活性的药物的作用，以保护神经元免受GP120诱导的损伤。可以预料，这些研究NMDAR在神经元细胞损伤中作用的临床前研究可能会导致对艾滋病神经系统表现的新处理。