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

该提案旨在研究一组分子的作用和作用机制，称为磷酸肌苷3-激酶（pi3k）。当细胞接收到外界信号时，pi3k在细胞内产生信号，使细胞作出反应。这种输出可以是非常多样化的，包括细胞增殖、生存和抵抗压力，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）主要关注所谓的PI3K的第一类亚群。针对I类pi3k的药物目前正在人类癌症的临床试验中进行测试。目前，尽管其他人进行了多年的研究，但对II类和III类pi3k知之甚少。过去，我们已经非常成功地发现了I类pi3k的作用以及它们在疾病中的靶向作用。我们现在已经开始了一项科学研究计划，以发现II类和III类PI3K的生物学作用，并确定它们如何在细胞内转导信号。我们将通过研究II类或III类pi3k失活的小鼠来实现这一目标，以揭示这些pi3k在生物体中的作用，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和这些未被充分研究的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，它将增强我们对基本生物现象的认识。在过去，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。该提案也有可能使行业受益，因为它可能确定pi3k作为开发药物的新靶点。从长远来看，这项研究很可能会导致对疾病过程的更好理解和新药的开发。该提案是一项正在进行的多学科研究项目的一部分，该项目与英国五所大学和英国皇家医学研究所以及国际合作者合作。

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.