Biology of Serine Proteases and Serpins

受调节的蛋白水解被用于驱动许多生物过程，包括细胞周期、细胞死亡和胚胎形成。它也被认为是介导复杂的大脑功能，如学习和记忆。因此，蛋白质水解调节的缺陷导致人类疾病如癌症和神经退行性疾病也就不足为奇了。这项资助的总体目标是了解涉及丝氨酸蛋白酶及其抑制剂（称为丝氨酸蛋白酶抑制剂）协调作用的调节蛋白水解机制。提出了三个具体的目标：1）为了测试的假设，丝氨酸蛋白酶抑制剂是一种前转化酶，丝氨酸蛋白酶，激活广泛的细胞和致病蛋白，包括激素，生长因子和毒力决定因子的抑制剂。2)为了鉴定参与黑化反应的丝氨酸蛋白酶， 哺乳动物凝血反应的类似物，也是蚊子抗疟能力的关键决定因素。3)对丝氨酸蛋白酶抑制剂功能进行基于RNAi的筛选，最终将导致鉴定涉及丝氨酸蛋白酶和丝氨酸蛋白酶抑制剂的新生物过程。这些研究将利用果蝇，它利用许多相同的分子和细胞机制，作为哺乳动物，学习一般原则，如何调节蛋白水解涉及丝氨酸蛋白酶和丝氨酸蛋白酶抑制剂用于不同的生物学目的。

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.