Biology of Serine Proteases and Serpins

丝氨酸蛋白酶和丝氨酸蛋白酶抑制剂的生物学

• 批准号: 6869656
• 负责人: CARL HASHIMOTO
• 金额: $ 35.27万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869656
• 关键词: Drosophilidae; RNA interference; antibody; arthropod genetics; enzyme activity; immune response; molecular biology; prohormone convertase; protease inhibitor; protein structure function; proteolysis; serine proteinases

Regulated proteolysis is used to drive many biological processes, including the cell cycle, cell death, and embryonic patterning. It is also thought to mediate complex brain functions such as learning and memory. Not surprisingly, then, defects in regulated proteolysis lead to human pathologies such as cancer and neurodegenerative disease. The overall goal of this grant is to understand the mechanisms of regulated proteolysis involving the coordinated action of serine proteases and their inhibitors called serpins. Three specific aims are proposed: 1) To test the hypothesis that a serpin is an inhibitor of proconvertases, serine proteases that activate a wide range of cellular and pathogenic proteins, including hormones, growth factors, and virulence determinants. 2) To identity serine proteases involved in the melanization reaction, an insect analogue of the mammalian blood clotting reaction and a critical determinant of malarial resistance in the mosquito. 3) To perform an RNAi-based screen for serpin function that ultimately will lead to the identification of new biological processes involving serine proteases and serpins. These studies will exploit Drosophila, which utilizes many of the same molecular and cellular mechanisms as mammals, to learn general principles of how regulated proteolysis involving serine proteases and serpins is used for diverse biological purposes.

调节蛋白水解作用用于驱动许多生物过程，包括细胞周期、细胞死亡和胚胎模式。人们还认为它可以调节学习和记忆等复杂的大脑功能。毫不奇怪，调节蛋白水解的缺陷会导致癌症和神经退行性疾病等人类疾病。该资助的总体目标是了解调节蛋白水解的机制，涉及丝氨酸蛋白酶及其抑制剂（丝氨酸蛋白酶抑制剂）的协调作用。提出了三个具体目标：1) 检验丝氨酸蛋白酶抑制剂是原转化酶抑制剂的假设，丝氨酸蛋白酶可激活多种细胞和致病蛋白，包括激素、生长因子和毒力决定子。 2）为了鉴定参与黑化反应的丝氨酸蛋白酶，昆虫 哺乳动物凝血反应的类似物，也是蚊子抗疟疾的关键决定因素。 3) 对丝氨酸蛋白酶抑制剂功能进行基于RNAi的筛选，最终将导致涉及丝氨酸蛋白酶和丝氨酸蛋白酶抑制剂的新生物过程的鉴定。这些研究将利用果蝇（果蝇利用许多与哺乳动物相同的分子和细胞机制）来了解涉及丝氨酸蛋白酶和丝氨酸蛋白酶抑制剂的调节蛋白水解如何用于不同生物学目的的一般原理。