Biology of Serine Proteases and Serpins

受调控的蛋白分解被用来驱动许多生物过程，包括细胞周期、细胞死亡和胚胎模式。它还被认为调节复杂的大脑功能，如学习和记忆。因此，毫不奇怪，调节蛋白分解的缺陷会导致人类的病理，如癌症和神经退行性疾病。这项资助的总体目标是了解调节蛋白分解的机制，涉及丝氨酸蛋白酶及其抑制物(称为蛇毒)的协调作用。提出了三个具体的目标：1)检验丝氨酸是原转化酶的抑制剂的假设，丝氨酸蛋白酶可以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素。2)为了鉴定参与黑化反应的丝氨酸蛋白酶，一种昆虫 哺乳动物凝血反应的类似物，也是蚊子抵抗疟疾的关键决定因素。3)进行基于RNAi的丝氨酸功能筛选，最终将导致鉴定涉及丝氨酸蛋白酶和丝氨酸酶的新的生物学过程。这些研究将利用果蝇，它利用了许多与哺乳动物相同的分子和细胞机制，以了解涉及丝氨酸蛋白酶和蛇的受调控的蛋白分解如何用于不同的生物目的的一般原理。

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.