Endothelin Converting Enzymes & Amyloid beta Catabolism

内皮素转换酶

• 批准号: 6685617
• 负责人: CHRISTOPHER B ECKMAN
• 金额: $ 25.6万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6685617
• 关键词: Alzheimer's disease; amyloid proteins; aspartic endopeptidases; clinical research; enzyme activity; enzyme deficiency; gene targeting; genetically modified animals; human tissue; immunocytochemistry; in situ hybridization; laboratory mouse; neuropathology; postmortem; protein metabolism

DESCRIPTION (provided by applicant): The abnormal accumulation of beta-amyloid (Abeta) in the brain is believed to play a pivotal role in the etiology and pathogenesis of Alzheimer's disease. As such, a major focus of AD research has been the elucidation of the mechanisms responsible for the generation of Abeta. As with any peptide, however, the degree of Abeta accumulation is dependent not only on its production but also on its removal. In cell based and in vitro models we have previously characterized endothelin-converting enzyme-1 (ECE-1) as an Abeta-degrading enzyme that appears to act intracellularly, thus limiting the amount of Abeta available for secretion. To determine the physiological significance of this activity we have analyzed Abeta levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both Abeta40 and Abeta42 were found in the brains these animals when compared to age matched, littermate controls. These data provide strong support for our working hypothesis that ECE activity limits Abeta accumulation in the brain. In this application we propose to further test this hypothesis and to determine whether these elevations in Abeta levels will result in deposition or an enhancement of deposition in mouse models. Additionally we propose to extend our analysis into human brain. Given the evidence that Abeta plays a significant role in AD pathogenesis, understanding those factors that can influence Abeta levels, such as ECE activity, may provide new insights into the disease and could provide novel therapeutic approaches. Equally important, ECE inhibitors are being developed as novel anti-hypertensives. Understanding the effects of chronic reductions in ECE activity has the additional advantage that it may shed light on a significant potential side effect of the use of these drugs that may not be observed in normal clinical trials.

描述（由申请人提供）：β-淀粉样蛋白（Abeta）在大脑中的异常积累被认为在阿尔茨海默病的病因学和发病机制中发挥着关键作用。因此，AD 研究的一个主要焦点是阐明 Abeta 产生的机制。然而，与任何肽一样，Abeta 积累的程度不仅取决于其产生，还取决于其去除。在基于细胞的体外模型中，我们之前已将内皮素转化酶-1 (ECE-1) 描述为一种 Abeta 降解酶，它似乎在细胞内起作用，从而限制了可分泌的 Abeta 量。为了确定这种活性的生理意义，我们分析了缺乏 ECE-1 和密切相关的酶 ECE-2 的小鼠大脑中的 Abeta 水平。与年龄匹配的同窝对照动物相比，这些动物大脑中 Abeta40 和 Abeta42 的水平显着增加。这些数据为我们的工作假设提供了强有力的支持，即 ECE 活动限制了 Abeta 在大脑中的积累。在本申请中，我们建议进一步检验这一假设，并确定 Abeta 水平的升高是否会导致小鼠模型中的沉积或沉积的增强。此外，我们建议将我们的分析扩展到人脑。鉴于 Abeta 在 AD 发病机制中发挥重要作用的证据，了解那些可能影响 Abeta 水平的因素（例如 ECE 活性）可能会为该疾病提供新的见解，并可能提供新的治疗方法。同样重要的是，ECE 抑制剂正在被开发为新型抗高血压药物。了解 ECE 活性长期减少的影响还有一个额外的好处，即它可能揭示使用这些药物的潜在副作用，而这些副作用在正常临床试验中可能观察不到。