HTS of Microglia for Clearance of Amyloid-Beta in Alzheimer's Disease

小胶质细胞的 HTS 清除阿尔茨海默病中的β淀粉样蛋白

• 批准号: 7329076
• 负责人: Josef Peter Klein
• 金额: $ 10万
• 依托单位: XACTAGEN, LLC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329076
• 关键词: Adverse effects; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Antibodies; Applications Grants; Biological Assay; Biological Factors; Biology; Brain; Caring; Cell Line; Cells; Chemicals; Clinical; Condition; Cultured Cells; Development; Disease; Disease Progression; Disease model; Emotional; Employee Strikes; Event; Exhibits; Facilities and Administrative Costs; Family; Goals; Human; Immune; Impaired cognition; Inflammatory; Institutionalization; Intervention; Laboratories; Lead; Libraries; Measures; Mediator of activation protein; Microglia; Mus; Neuraxis; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Phagocytosis; Pharmaceutical Preparations; Phase; Production; Prostaglandins; Reactive Nitrogen Species; Reactive Oxygen Species; Research Design; Robotics; Screening procedure; Signal Transduction; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Testing; Therapeutic; United States; Universities; Vaccines; Washington; amyloid peptide; base; brain tissue; chemokine; clinically relevant; concept; cost; cyclooxygenase 2; cytokine; design; drug discovery; high throughput screening; human NOS2A protein; mouse model; neuroinflammation; neurotoxic; neurotoxicity; novel strategies; peptide A; prevent; receptor; research study; response; small molecule; small molecule libraries

DESCRIPTION (provided by applicant): The amyloid hypothesis of Alzheimer's disease (AD) proposes that the primary event in AD pathogenesis correlating with disease progression and cognitive decline is the accumulation of amyloid-¿ peptide (A¿?) an abnormally expressed fragment of the amyloid precursor protein. Accordingly, approaches to slow AD progression are designed to prevent central nervous system (CNS) accumulation of A¿, either by pharmacological inhibition of its synthesis or by development of A¿ vaccines and antibodies that augment clearance of A¿ by microglia. Moreover, a secondary event in disease pathology results from release of proinflammatory cytokines, chemokines, and neurotoxic reactive oxygen species (ROS) and reactive nitrogen species (RNS) by microglia in response to activation by A¿. Although several drug discovery approaches show promise in suppressing A¿ ??accumulation, drug candidates derived from many of these approaches have side effects that remain problematic. In this SBIR study, we will discover agents which target unexploited pathways to both promote the reduction of A¿ in AD brain and suppress the associated neuroinflammation. Specifically, we will: 1) Develop high throughput assays using human microglial cell lines to measure A¿ phagocytosis and screen small molecule libraries of known drugs, bioactives and drug-like compounds to discover compounds that promote A¿ phagocytosis, 2) Develop assays to measure production of mediators of neuroinflammation and test whether compounds found to augment A¿ phagocytosis can suppress production of A¿ induced mediators of neuroinflammation in human microglial cell lines and primary human microglia, and 3) Compounds found to augment A¿ induced phagocytosis and suppress A¿ induced mediators of neuroinflammation in cell culture are tested for their ablility to induce primary human microglia to clear A¿ from clinically relevant post-mortem brain tissues obtained from AD patients. After completion of this Phase I project, the necessary AD assays, proof of concept for small molecule intervention, and required expertise for additional studies will be in place for identification and optimization of lead drug candidates in Phase II. Project In the United States, 4.5 million people have Alzheimer's Disease (AD) where direct and indirect costs of care are estimated at $100 billion annually. The disease is currently not curable and is the leading cause of institutionalization. Emotional costs to families are considerable. Our SBIR studies are designed to probe new avenues to arrive at effective drug treatments for AD. Public

描述（由申请人提供）：阿尔茨海默病（AD）的淀粉样蛋白假说提出，与疾病进展和认知能力下降相关的AD发病机制的主要事件是淀粉样蛋白前体蛋白异常表达片段淀粉样蛋白-肽（A¿？）的积累。因此，减缓阿尔茨海默病进展的方法被设计为防止中枢神经系统（CNS） A¿的积累，要么通过药理抑制其合成，要么通过开发A¿疫苗和抗体来增强小胶质细胞对A¿的清除。此外，疾病病理中的次要事件是小胶质细胞在响应a¿激活时释放促炎细胞因子、趋化因子和神经毒性活性氧（ROS）和活性氮（RNS）。尽管几种药物发现方法显示出抑制A¿？？积累，从许多这些方法衍生的候选药物有副作用，仍然存在问题。在这项SBIR研究中，我们将发现靶向未开发途径的药物，既可以促进AD大脑中A¿的减少，又可以抑制相关的神经炎症。具体而言，我们将：1)利用人小胶质细胞系开发高通量测定A¿吞噬的方法，筛选已知药物、生物活性物质和药物样化合物的小分子文库，以发现促进A¿吞噬的化合物；2)开发测定神经炎症介质的产生的方法，并测试在人小胶质细胞系和原代人小胶质细胞中发现的增强A¿吞噬的化合物是否可以抑制A¿诱导的神经炎症介质的产生；3)在细胞培养中发现了增强A¿诱导的吞噬和抑制A¿诱导的神经炎症介质的化合物，并对其诱导原代人小胶质细胞清除AD患者临床相关死后脑组织中的A¿的能力进行了测试。在I期项目完成后，将进行必要的AD分析、小分子干预的概念验证以及其他研究所需的专业知识，以确定和优化II期的主要候选药物。在美国，有450万人患有阿尔茨海默病（AD），每年的直接和间接护理费用估计为1000亿美元。这种疾病目前无法治愈，是机构化的主要原因。家庭的情感成本是相当大的。我们的SBIR研究旨在探索新的途径，以达到有效的药物治疗阿尔茨海默病。公共