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：
8680099
负责人：
DAVID R SCHUBERT
金额：
$ 37.54万
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 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8680099
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 cognitive impairment new therapeutic target prevent protein aggregate 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.

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还没有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）的激活在神经细胞中发挥着核心作用。死亡与这两种疾病相关，因为在细胞培养研究和模拟这些疾病的动物模型中，LOX抑制剂减少了神经细胞死亡。此外，LOX在AD和轻度认知障碍以及其中各种AD转基因动物中高度升高。 LOX 和提供 LOX 底物的磷脂酶被基因删除，从而大大减少了病理学。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 LOX 代谢的 CNS 疗法也尚未得到广泛测试。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细胞培养模型中研究 LOX 介导的神经细胞死亡。此外，LOX 抑制剂可增强与 AD 和衰老相关的聚集蛋白的去除，我们将使用这些实验系统回答以下问题。谷胱甘肽激活 LOX，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 产物有哪些？如何抑制？ LOX酶活性的增加会增加细胞内聚集的淀粉样蛋白的清除率并促进细胞存活吗？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代谢中的作用奠定坚实的基础。淀粉样蛋白，在动物中测试这一途径，并确定新的治疗靶点。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A comprehensive multiomics approach toward understanding the relationship between aging and dementia.

DOI：
10.18632/aging.100838
发表时间：
2015-11
期刊：
Aging
影响因子：
0
作者：
Currais A;Goldberg J;Farrokhi C;Chang M;Prior M;Dargusch R;Daugherty D;Armando A;Quehenberger O;Maher P;Schubert D
通讯作者：
Schubert D

A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease.

DOI：
10.1371/journal.pone.0027865
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Chen Q;Prior M;Dargusch R;Roberts A;Riek R;Eichmann C;Chiruta C;Akaishi T;Abe K;Maher P;Schubert D
通讯作者：
Schubert D

The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice.