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Pan-Lipoxygenase Inhibitors for CNS Disease

治疗中枢神经系统疾病的泛脂氧合酶抑制剂

基本信息

批准号：
7986374
负责人：
DAVID R SCHUBERT
金额：
$ 39.05万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7986374
关键词：
Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Animal Model Animals Antioxidants Apoptosis Arachidonate 12-Lipoxygenase Arachidonate 15-Lipoxygenase Arachidonate 5-Lipoxygenase Asthma Behavior Behavioral Biological Assay Brain Categories Cell Culture Techniques Cell Death Cell Survival Cells Central Nervous System Diseases Chronic Clinic Disease Electron Transport Enzymes Excision Foundations Gene Deletion Genes Glucose Glutamates Glutathione Goals Human Huntington Disease In Vitro Inflammation Ischemia Ischemic Stroke Knock-out Knockout Mice Lead Lipoxygenase Lipoxygenase Inhibitors Literature Mass Spectrum Analysis Mediating Memory impairment Metabolic Metabolic Clearance Rate Metabolism Mitochondria Modeling Molecular Molecular Biology Molecular Target Mus Nerve Cell Survival Nervous System Trauma Nervous system structure Neurodegenerative Disorders Neurons Oryctolagus cuniculus Oxidative Stress Parkinson Disease Pathology Pathway interactions Pharmaceutical Preparations Phospholipase Phosphoproteins Phosphorylation Play Preclinical Drug Evaluation Procedures Production Prostaglandin-Endoperoxide Synthase Proteins Proteomics Reactive Oxygen Species Reporting Role Sclerosis Screening procedure Series Signal Pathway Site Solid Starvation Stroke Substrate Specificity System Technology Testing Toxic effect Toxin Transgenic Animals Transgenic Mice Transgenic Organisms Withdrawal Work age related base defined contribution design drug candidate drug development effective therapy excitotoxicity extracellular fatty acid metabolism insight lipid metabolism mild neurocognitive impairment new therapeutic target prevent protein aggregate public health relevance research study small molecule therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): There are currently no effective cures or treatments for chronic CNS conditions such as Alzheimer's disease (AD) and stroke. We and others have shown that the activation of lipoxygenases (LOXs) play a central role in the nerve cell death associated with both disorders because LOX inhibitors reduce nerve cell death in both cell culture studies and in animal models that mimic these disorders. Furthermore, LOXs are highly elevated in AD and mild cognitive impairment, and AD transgenic animals in which the various LOXs and the phospholipases that provide LOX substrates are genetically deleted have greatly reduced pathology. However, the molecular mechanisms by which LOX enzymes are activated and how their products cause nerve cell death are unknown. Nor have CNS therapies based upon LOX metabolism been extensively tested in animal models. To understand the signaling pathways and gain better insight into potential therapeutic targets, we will study LOX-mediated nerve cell death in two robust cell culture models of chronic oxidative stress and intracellular beta amyloid toxicity. Both paradigms are associated with the depletion of glutathione and ROS production. In addition, LOX inhibitors enhance the removal of aggregated protein, a condition associated with AD and aging in general. Using these experimental systems, we will answer the following questions. What is the mechanism by which the depletion of glutathione activates LOXs and how do the LOX metabolites stimulate ROS production from mitochondria? What are the specific LOX products involved in both ROS production and the cell death pathways? What are the molecular signaling pathways involved? How does the inhibition of LOX enzymatic activity increase the rate of clearance of aggregated intracellular amyloid and promote cell survival? Finally, we will determine if our best pan-LOX inhibitor is able to clear intracellular A¿, reduce AD pathology and behavioral deficits in a transgenic mouse AD model and define the contribution of the major LOX genes to AD pathology. These experiments will build a solid foundation for the role of LOX metabolism in nerve cell death and the metabolism of intracellular amyloid, test this pathway in animals, and identify new therapeutic targets. PUBLIC HEALTH RELEVANCE: There are no cures or effective treatments for Alzheimer's disease or stroke, nor is it understood how and why nerve cells die in these conditions. On the basis of a very rigorous screening procedure we have identified a series of drug-like small molecules that are effective in animal models of Alzheimer's and stroke, but we do not understand the molecular pathways by which they are neuroprotective. To push these drugs to the clinic and to identify more and perhaps better therapeutic targets, we need to understand exactly how these drugs function, and that is the goal of this proposal.

描述（由申请人提供）：目前对于阿尔茨海默病（AD）和中风等慢性中枢神经系统疾病尚无有效的治愈或治疗方法。我们和其他人已经证明，脂氧合酶 (LOX) 的激活在与这两种疾病相关的神经细胞死亡中发挥着核心作用，因为在细胞培养研究和模拟这些疾病的动物模型中，LOX 抑制剂可减少神经细胞死亡。此外，LOX在AD和轻度认知障碍中高度升高，而AD转基因动物（其中各种LOX和提供LOX底物的磷脂酶被基因删除）的病理学大大减少。然而，LOX 酶被激活的分子机制及其产物如何导致神经细胞死亡尚不清楚。基于液氧代谢的中枢神经系统疗法也没有在动物模型中进行过广泛测试。为了了解信号通路并更好地了解潜在的治疗靶点，我们将在慢性氧化应激和细胞内 β 淀粉样蛋白毒性的两种稳健的细胞培养模型中研究 LOX 介导的神经细胞死亡。这两种模式都与谷胱甘肽的消耗和活性氧的产生有关。此外，LOX 抑制剂可增强聚集蛋白的去除，聚集蛋白是一种与 AD 和衰老相关的疾病。使用这些实验系统，我们将回答以下问题。谷胱甘肽的消耗激活 LOX 的机制是什么？LOX 代谢物如何刺激线粒体产生 ROS？参与 ROS 产生和细胞死亡途径的具体 LOX 产品有哪些？涉及哪些分子信号通路？抑制LOX酶活性如何提高聚集的细胞内淀粉样蛋白的清除率并促进细胞存活？最后，我们将确定我们最好的泛 LOX 抑制剂是否能够清除细胞内 A¿，减少转基因小鼠 AD 模型中的 AD 病理和行为缺陷，并确定主要 LOX 基因对 AD 病理的贡献。这些实验将为LOX代谢在神经细胞死亡和细胞内淀粉样蛋白代谢中的作用奠定坚实的基础，在动物中测试该途径，并确定新的治疗靶点。公共健康相关性：阿尔茨海默病或中风尚无治愈或有效的治疗方法，也不了解神经细胞在这些情况下如何以及为何死亡。在非常严格的筛选程序的基础上，我们已经确定了一系列对阿尔茨海默氏症和中风动物模型有效的类药物小分子，但我们不了解它们具有神经保护作用的分子途径。为了将这些药物推向临床并确定更多甚至更好的治疗靶点，我们需要准确了解这些药物的作用原理，这就是该提案的目标。