Vasopeptidases and Beta Amyloid Accumulation

血管肽酶和β淀粉样蛋白积累

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

描述（由申请人提供）：血管肽酶是负责血管活性肽的产生或失活的酶。因此，血管肽酶抑制是一种治疗心血管疾病的重要方法。例如，血管紧张素转换酶（ACE）抑制剂已获得FDA批准，并广泛用于治疗高血压和心力衰竭。此外，其他两种血管肽酶Neprilysin（NEP）和内皮素转换酶（ECE）的抑制剂目前处于临床前和临床发育中，这是这些酶的合并抑制剂。最近，出现了大量数据，表明血管肽酶ECE和NEP以及ACE在阿尔茨海默氏症的淀粉样蛋白β-肽（ABETA）降解中起作用。由于Abeta的异常积累在AD发病机理中起关键作用，因此对这些血管肽酶的药理抑制作用引起了人们的关注，因为它们可能会增加ABETA水平，从而增加患阿尔茨海默氏病的风险。在此应用中，我们建议直接评估ECE，NEP和ACE的慢性降低将通过检查小鼠在这些酶和用临床上相关的血管肽酶抑制剂治疗的小鼠中的作用来提高ABETA积累和类似AD的病理的假设。这些研究的结果将进一步了解NEP，ECE和ACE在确定大脑中ABETA浓度方面的作用，同时帮助评估血管肽酶抑制剂临床使用的潜在风险。