Vasopeptidases and Beta Amyloid Accumulation

血管肽酶和β淀粉样蛋白积累

• 批准号: 7407399
• 负责人: STEVEN G YOUNKIN
• 金额: $ 27.01万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407399
• 关键词: Acute; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Angiotensin-Converting Enzyme Inhibitors; Animals; Brain; Cardiovascular Diseases; Cerebrum; Chronic; Clinical; Data; Development; Doctor of Philosophy; Elevation; Endopeptidases; Endothelin-converting enzyme 1; Engineering; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Generations; Heart failure; Human; Hypertension; In Vitro; Investigational Drugs; Knockout Mice; Lead; Mus; Neprilysin; Pathogenesis; Pathology; Pathology, Other; Peptide Hydrolases; Peptides; Peptidyl-Dipeptidase A; Physiological; Plasma; Play; Protein Overexpression; Research Personnel; Risk; Role; Senile Plaques; Staging; Tg2576; United States Food and Drug Administration; Wild Type Mouse; abeta accumulation; age related; clinically relevant; cohort; endothelin converting enzyme-2; endothelin-converting enzyme; enzyme deficiency; inhibitor/antagonist; knockout gene; mouse model; pre-clinical; programs

DESCRIPTION (provided by applicant): Vasopeptidases are enzymes responsible for the generation or inactivation of vasoactive peptides. As such, vasopeptidase inhibition represents a significant approach for the treatment of cardiovascular disease. For example, angiotensin-converting enzyme (ACE) inhibitors are FDA approved and widely used to treat hypertension and heart failure. In addition, inhibitors of two other vasopeptidases, neprilysin (NEP) and endothelin-converting enzyme (ECE), are currently in preclinical and clinical development as are combined inhibitors of these enzymes. Recently, considerable data has emerged indicating a role for the vasopeptidases ECE and NEP, and perhaps also ACE, in the degradation of the Alzheimer's amyloid beta-peptide (ABeta). As the abnormal accumulation of ABeta plays a pivotal role in AD pathogenesis, pharmacological inhibition of these vasopeptidases is of considerable concern as they may increase ABeta levels in a manner that increases risk of developing Alzheimer's disease. In this application we propose to directly evaluate the hypothesis that chronic reductions in ECE, NEP, and ACE will result in enhanced ABeta accumulation and AD-like pathology by examining the effects of mice genetically deficient in these enzymes and mice treated with clinically relevant vasopeptidase inhibitors. The results of these studies will further our understanding of the role of NEP, ECE, and ACE in determining ABeta concentration in the brain, while helping to assess the potential risk of the clinical use of vasopeptidase inhibitors.

性状（由申请方提供）：血管肽酶是负责血管活性肽生成或失活的酶。因此，血管肽酶抑制代表了治疗心血管疾病的重要方法。例如，血管紧张素转换酶（ACE）抑制剂是FDA批准的并且广泛用于治疗高血压和心力衰竭。此外，另外两种血管肽酶，脑啡肽酶（NEP）和内皮素转化酶（ECE）的抑制剂目前正处于临床前和临床开发中，这些酶的组合抑制剂也是如此。最近，大量的数据表明血管肽酶ECE和NEP，也许还有ACE，在阿尔茨海默氏症淀粉样β肽（ABeta）的降解中的作用。由于ABeta的异常积累在AD发病机制中起关键作用，因此这些血管肽酶的药理学抑制是相当令人关注的，因为它们可能以增加发展阿尔茨海默病的风险的方式增加ABeta水平。在本申请中，我们建议通过检查遗传缺陷小鼠和临床相关血管肽酶抑制剂治疗小鼠的影响，直接评估ECE、NEP和ACE慢性减少将导致ABeta蓄积增强和AD样病理学的假设。这些研究的结果将进一步加深我们对NEP、ECE和ACE在确定脑中ABeta浓度中的作用的理解，同时有助于评估血管肽酶抑制剂临床使用的潜在风险。