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UK funding (£551,151): The role and mechanism of action of p110delta PI3K signalling in gastrointestinal immunity and inflammation. Ukri1 Jun 2015 UK Research and Innovation, United Kingdom
Overview
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The role and mechanism of action of p110delta PI3K signalling in gastrointestinal immunity and inflammation.
| Abstract | This proposal seeks to investigate the roles and mechanism of function of a group of enzymes, known as phosphoinositide 3-kinases (PI3Ks), in mammalian gut immunity and inflammation. PI3K enzymes generate second messengers that transmit signals inside cells, controlling a large number of important biological functions including cell division, proliferation, and motility but also stress response and host defence against danger signals of either microbial or environmental origin. There are three subgroups of the PI3K family, class I, II and III, which the class I PI3Ks are the best characterized family members. Some of the class I PI3Ks are mutated in certain human disease and inhibitors of these enzymes are currently being tested in clinical trials in cancer, airway inflammation and overgrowth syndromes. A full appreciation of the biochemistry of cell communication systems is therefore important to understand central physiological and patho-physiological processes associated in human diseases such as inflammatory bowel disease (IBD). Host innate defences are generated by a set of pathogen recognition molecules (PRMs), which tailor protective immune responses by detecting and alerting the microbial activity and pathogenicity in the intestinal environment. The innate defences in this anatomical location consist of professional phagocytes and epithelial cells that are equipped with, NOD1 and/or NOD2, an important family of PRMs detecting microbial products and maintaining tolerance to the commensals microorganisms. In general, host commensal microorganisms in the gut do not lead to IBD in healthy individuals, indicating that host tolerance to microorganisms is achieved by healthy host-microbe interplay. Mutations causing inactivation of the gene encoding the NOD2 results in Crohn's disease, a type of IBD in humans. PI3K pathway has been implicated in host defence and inflammation, but their role in gut health and chronic IBD remains not well understood. We therefore propose to investigate the roles of PI3K enzymes in animal models of intestinal inflammation with the potential to unravel the basic biological processes driving IBD pathology involving commensal microorganisms. A key and unique tool in our studies is a panel of unique mouse strains in which specific PI3K genes have been genetically inactivated. Using these mice, we have evidence that a single member of the PI3K family positively controls host defence to gut microbiota and hence protects against IBD. Pharmaceutical drugs that inhibit one or several of these enzymes are in clinical trials or have been approved for treatment of diseases including cancer and airway inflammation, but were reported to cause colitis as side effects, similar to the pathology observed in PI3K-targeted mice. This is a fundamental and multi-disciplinary study that can contribute to greater understanding of key immunological and medical phenomena. The longer term impacts of this work may contribute to the greater understanding of major socio-economically relevant diseases, including inflammatory bowel disease and arthritis, reported to be linked to deregulated immune response to commensal microorganisms. Our preliminary findings suggest PI3Ks are important players in intestinal homeostasis and thus are good targets for therapeutic modulation. This project has the potential to benefit pharmaceutical industry, as it can reveal aetiologies underlying colitis susceptibility to PI3K inhibitors in humans and in the longer term might identify specific PI3K isoforms as new targets to develop therapeutics angles. |
| Category | Research Grant |
| Reference | MR/M023230/1 |
| Status | Closed |
| Funded period start | 01/06/2015 |
| Funded period end | 16/06/2019 |
| Funded value | £551,151.00 |
| Source | https://gtr.ukri.org/projects?ref=MR%2FM023230%2F1 |
Participating Organisations
| Queen Mary University of London | |
| QUEEN MARY UNIVERSITY OF LONDON | |
| University College London | |
| Necker-Enfants Malades Hospital | |
| London School of Hygiene and Tropical Medicine (LSHTM) | |
| Institut Necker Enfants Malades (INEM) |
The filing refers to a past date, and does not necessarily reflect the current state. The current state is available on the following page: Queen Mary University of London, London.
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