Development of Myeloperoxidase Inhibitors to Treat Alzheimer's Disease

开发治疗阿尔茨海默病的髓过氧化物酶抑制剂

• 批准号: 8315644
• 负责人: Richard Allan Maki
• 金额: $ 25.51万
• 依托单位: TORREY PINES PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8315644
• 关键词: Alu Elements; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Astrocytes; Atherosclerosis; Autopsy; Behavioral; Binding Sites; Biochemical; Bone Marrow; Brain; Cell Death; Clinical; Cognitive; Cognitive deficits; Deposition; Development; Disease; Disease Progression; Elements; Enzymes; Event; Foam Cells; Free Radicals; Gene Expression; Genes; Goals; Human; Hypochlorous Acid; Immune system; Infection; Inflammatory; Iron; Lead; Leukocytes; Lipid Peroxidation; Lipids; Memory Loss; Mitochondria; Modeling; Mus; Myelogenous; Neurons; Nitrates; Nitrogen Dioxide; Normal Cell; Nuclear Receptors; Nucleic Acids; Oxidants; Oxygen Consumption; Pathology; Patients; Peroxidases; Pharmaceutical Preparations; Phase; Phospholipids; Primates; Property; Proteins; Reactive Oxygen Species; Research; Role; Senile Plaques; Site; Small Business Innovation Research Grant; Source; Staging; Testing; Therapeutic Agents; Tissues; Transgenes; Transgenic Mice; Tyrosine; Unsaturated Fatty Acids; base; cancer cell; chlorination; high throughput screening; improved; inhibitor/antagonist; macrophage; member; mild neurocognitive impairment; monocyte; mouse model; neutrophil; novel; novel therapeutics; oxidation; oxidative damage; peroxidation; promoter; research study; small molecule libraries; transcription factor

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to develop orally active inhibitors of myeloperoxidase MPO as a treatment forAlzheimer's disease. MPO is an abundant enzyme in leukocytes but its expression can be induced in astrocytes in Alzheimer's disease. This abnormal expression of MPO can lead to the oxidation of lipids and proteins leading to tissue damage and cell death resulting in loss of memory. A potent and safe inhibitor of MPO could be helpful in the treatment of Alzheimer's disease. We have developed novel mouse model to evaluate the role of MPO in Alzheimer's disease. In Specific Aim 1 We propose to improve the potency of hits identified in a screen looking for inhibitors of MPO. In Specific Aim 2 we propose to test several of the MPO inhibitors in a mouse model of Alzheimer's disease. The mice will be evaluated using both biochemical and behavioral/cognitive tests. PUBLIC HEALTH RELEVANCE: Myeloperoxidase is recognized as an important causative contributory agent in inflammatory diseases including Alzheimer's disease. An inhibitor of myeloperoxidase would provide a novel therapeutic agent that could be used to lower the level of oxidative damage that occurs in Alzheimer's disease. The experiments outlined in this Phase I SBIR application will help set the stage for the development of a novel and safe myeloperoxidase inhibitor for clinical use.

描述(由申请人提供)：拟议研究的总体目标是开发口服活性的髓过氧化物酶MPO抑制剂作为治疗阿尔茨海默病的药物。MPO是白细胞中含量丰富的一种酶，但在阿尔茨海默病患者的星形胶质细胞中可以诱导其表达。MPO的这种异常表达可导致脂质和蛋白质的氧化，导致组织损伤和细胞死亡，从而导致记忆丧失。一种有效且安全的MPO抑制剂可能有助于阿尔茨海默病的治疗。我们开发了新的小鼠模型来评估MPO在阿尔茨海默病中的作用。在具体目标1中，我们建议提高在寻找MPO抑制剂的屏幕上识别的命中的效力。在具体目标2中，我们建议在阿尔茨海默病小鼠模型中测试几种MPO抑制剂。这些小鼠将通过生化和行为/认知测试进行评估。 公共卫生相关性：髓过氧化物酶被认为是包括阿尔茨海默病在内的炎症性疾病的重要致病因素。髓过氧化物酶的抑制剂将提供一种新的治疗剂，可用于降低阿尔茨海默病中发生的氧化损伤水平。第一阶段SBIR应用中概述的实验将有助于为临床使用的新型安全髓过氧化物酶抑制剂的开发奠定基础。