Isoforms of PI 3-kinase as novel regulators of dsRNA-sensing and inflammation

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This proposal seeks to investigate the roles of important regulators of fundamental processes inside mammalian cells, called phosphoinositide 3-kinases (or PI3Ks in short). One function of PI3Ks is to transmit signals from the outside to the inside of cells, and make the cells respond in appropriate ways. This process is called signal transduction. Another function is to remodel intracellular membranes to control a process called vesicular trafficking. Signal transduction and vesicular trafficking are interconnected, but much needs to be learned about how this works. Mammalian cells have eight family members of PI3K, divided in three subgroups. An important scientific question is to clarify the functions of the different PI3K family members and find out how they work. Thus far, scientists have mainly studied the group I PI3Ks and discovered specialised functions of the different family members, both in healthy tissue and in cancer, inflammation and diabetes. Drugs against group I PI3Ks are currently being tested in clinical trials in human cancer and allergy. The group III PI3K has been shown to be important for the distribution and processing of materials taken up by cells, as well as for a process called self-eating that helps to keep the cell clean and organized. At the moment, very little is known about the group II PI3Ks, especially about the processes they control in cells and whether they could be useful drug targets. In this proposal, we plan to explore novel functions of the group II PI3Ks, and to find out how they carry out these roles at the cellular level. In exploratory studies, we have identified an important signal transduction process in which vesicular traffic and the group II PI3K appear to be involved. This is the detection of so-called pathogen-associated molecular patterns (PAMPs) by Toll-like receptors. These serve as detectors of foreign invaders exhibiting such PAMPs, such as viruses and bacteria, and are crucial for our body's immune response. These receptors have also been implicated in how vaccines work and more recently, in cancer. Some of these discoveries have been made by studying mice in which PI3Ks have been inactivated, in order to uncover what these PI3Ks do in the living organism, and how they work. We believe that our proposed studies can clarify the mechanism by which group II PI3Ks control the interplay of endosomal traffic and the signalling by Toll-like receptors. This might, in future, provide the rationale to develop drugs that could interfere with these processes, to ultimately combat diseases where the immune system is deregulated, such as inflammatory conditions. This is a fundamental science proposal that will enhance our knowledge about basic biological phenomena. In the longer term, it is possible that this research may lead to a better understanding of disease processes and to the development of new medicines.