STRUCTURE/FUNCTION ALZHEIMERS DISEASE PROTEASE INHIBITOR

结构/功能 阿尔茨海默病蛋白酶抑制剂

• 批准号: 3487901
• 负责人: BARBARA L CORDELL
• 金额: $ 5万
• 依托单位: CALIFORNIA BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-11 至 1990-11-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3487901
• 关键词: Alzheimer's disease; Escherichia coli; affinity chromatography; amyloid proteins; computer simulation; genetic manipulation; high performance liquid chromatography; molecular cloning; neuritic plaques; nuclear magnetic resonance spectroscopy; plasmids; protease inhibitor; protein biosynthesis; protein purification; protein sequence; protein structure function

Approximately 5% of the over 65 population in the U.S. suffers from Alzheimer's disease (AD). Despite its prevalence no efficacious treatment exist. Definitive diagnosis is made on autopsy using the histopathological hallmark of the disease - amyloid deposition in the brain and cerebrovasculature. Amyloid deposition occurs at a frequency 1000-fold greater than in a normal aged brain. Amyloid is derived from a larger precursor protein, an alternative form of which harbors a Kunitz protease inhibitor. Because amyloid is derived via proteolytic cleavage, the function of the inhibitor domain may have a critical role in both the normal and pathological condition. The aim of phase I is to recombinantly produce homogeneous inhibitor suitable for three-dimensional structural analysis. Phase II will be aimed at resolving the tertiary structure of the inhibitor, identifying its target protease, and determining its functional role in the proteolytic processing of the amyloid precursor. Structural and functional knowledge may provide a rationale for therapeutic intervention in AD.

在美国65岁以上的人口中，大约5%的人患有 阿尔茨海默病(AD)。尽管它很流行，但没有有效的治疗方法 是存在的。最终的诊断是通过尸检和组织病理学做出的。 这种疾病的特征是大脑和大脑中的淀粉样蛋白沉积 脑血管病。淀粉样蛋白沉积的频率为1000倍 比正常老化的大脑要大。淀粉样蛋白来源于一种较大的 前体蛋白，其另一种形式含有库尼茨蛋白酶 抑制剂。由于淀粉样蛋白是通过蛋白水解性裂解而来的，所以 抑制物结构域的功能可能在这两个过程中起关键作用 正常和病理状态。第一阶段的目标是重组 生产适用于三维结构的均质缓蚀剂 分析。第二阶段的目标是解决 抑制物，鉴定其目标蛋白水解酶，并测定其 淀粉样前体蛋白分解过程中的功能作用。 结构和功能知识可能为治疗提供理论基础 对AD的干预。