Signalling and biological roles of the class II and III PI 3-kinase enzymes

这项提议试图研究一组分子的作用和作用机制，这些分子被称为磷脂酰肌醇3-激酶(PI3K)。当细胞接收到来自外界的信号时，PI3K会在细胞内产生信号，使细胞做出反应。这种输出可以是非常多样化的，包括细胞增殖、存活和对压力的抵抗力，但也包括激素的产生、细胞迁移甚至细胞死亡。PI3K通路与癌症、炎症、自身免疫和糖尿病等疾病有关。因此，这一途径被认为是药物开发的一个有趣的新靶点。PI3K有三个亚群，到目前为止，科学家(包括我们自己)主要关注PI3K的所谓I类子集。针对I类PI3K的药物目前正在进行人类癌症的临床试验。目前，尽管其他人进行了多年的研究，但人们对II级和III级PI3K知之甚少。在过去，我们非常成功地发现了第一类PI3K正在做什么，以及他们如何成为疾病的靶点。我们现在已经开始了一项科学研究计划，以找出第二类和第三类PI3K的生物学作用，并确定它们如何在细胞内传递信号。我们将通过研究II或III类PI3K被灭活的小鼠来实现这一点，以揭示这些PI3K在活的有机体中起什么作用，以及它们是如何工作的。我们已经做了一些有趣的初步观察，现在建议对这些小鼠以及这些研究较少的PI3K家族成员的作用机制进行全面的描述。这是一个基础科学项目，将增进我们对基本生物现象的了解。过去，PI3K的生物学对科学的影响远远超出了我们自己的领域，主要是因为这些酶控制着生物学的基础。这项提议也有可能使行业受益，因为它可能会将PI3K确定为开发针对药物的新目标。从长远来看，这项研究很有可能导致对疾病过程的更好理解和新药的开发。这项提议是与五所英国大学和CRUK的合作者以及国际合作者正在进行的多学科研究项目的一部分。

This proposal seeks to investigate the roles and mechanism of action of a group of molecules, known as phosphoinositide 3-kinases (PI3Ks). When cells receive signals from the outside world, PI3Ks generate signals inside cells to make the cells respond. This output can be very diverse, and includes cell proliferation, survival and resistance against stress, but also the production of hormones, cell migration or even cell death. The PI3K pathway has been implicated in diseases such as cancer, inflammation, auto-immunity and diabetes. This pathway is therefore considered as an interesting new target for drug development. There are three subgroups of PI3K and thus far, scientists (including ourselves) have mainly focused on the so-called class I subset of PI3Ks. Drugs against the class I PI3Ks are currently being tested in clinical trials in human cancer. At the moment, very little is known about the class II and III PI3Ks, despite many years of research by others. We have in the past been very successful in finding out what the class I PI3Ks are doing and how they can be targeted in disease. We have now embarked on a scientific research programme to find the biological roles of the class II and III PI3K, and to identify how they transduce signals inside cells. We will do this by studying mice in which the class II or III PI3Ks have been inactivated, in order to uncover what these PI3Ks do in the living organism, and how they work. We have made some interesting initial observations, and now propose to progress to a full characterisation of these mice and the mechanism of action of these poorly-investigated members of the PI3K family. This is a fundamental science project that will enhance our knowledge about basic biological phenomena. In the past, the biology of PI3Ks has impacted on science far beyond our own field, mainly because these enzymes control fundamentals of biology. This proposal also has the potential to benefit industry, as it might identify PI3Ks as new targets to develop medicines against. In the longer term, it is very likely that this research may lead to a better understanding of disease processes and to the development of new medicines. This proposal is part of an ongoing, multidisciplinary research project with collaborators at five UK Universities and CRUK, as well as international collaborators.