ACUTE GAMMA-SECRETASE INHIBITION OF NONHUMAN PRIMATE CNS SHIFTS AMYLOID

非人类灵长类中枢神经系统淀粉样蛋白的急性伽马分泌酶抑制

• 批准号: 8361448
• 负责人: RANDALL J BATEMAN
• 金额: $ 0.43万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361448
• 关键词: Acute; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Brain; Development; Enzyme Inhibition; Enzymes; Funding; Goals; Grant; Human; Kinetics; Macaca mulatta; Mass Spectrum Analysis; Methods; Modeling; Molecular Mechanisms of Action; National Center for Research Resources; Physiological Processes; Physiology; Principal Investigator; Production; Reporting; Research; Research Infrastructure; Resources; Source; Stable Isotope Labeling; Testing; Translations; United States National Institutes of Health; abeta accumulation; beta secretase; biomedical resource; cisterna magna; cost; extracellular; gamma secretase; in vivo; inhibitor/antagonist; nonhuman primate; protein metabolite

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The accumulation of amyloid beta (Abeta) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble Abeta species and extracellular plaque formation in the brain. Multiple Abeta-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Abeta, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Abeta physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a gamma-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Abeta (beta- and gamma-secretase) is that precursors of Abeta may accumulate and cause a rapid increase in Abeta production when enzyme inhibition discontinues.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 阿尔茨海默病中淀粉样蛋白β（Abeta）的积累是由产生和清除的不平衡引起的，这导致可溶性Abeta种类增加和脑中细胞外斑块形成。目前正在开发多种降低A β的疗法：一个重要的目标是在接近人类A β生理学的模型中表征作用的分子机制和对A β生理学加工的影响，以及其他淀粉样前体蛋白（APP）代谢物。为此，我们报告翻译的人在体内稳定同位素标记动力学（SILK）方法的恒河猴枕大池移植（CMP）非人灵长类动物模型，并使用该模型来测试的γ-分泌酶抑制剂（GSI）的作用机制。抑制产生Abeta（β-和γ-分泌酶）的酶的一个主要问题是Abeta的前体可能积累并在酶抑制停止时引起Abeta产生的快速增加。