Investigation of Metabolic and Growth-related Diseases Associated with Mutations in Phosphoinositide-3-kinase, Catalytic, Alpha Polypeptide (PIK3CA). (360G-Wellcome-097721_Z_11_Z)
Dysregulation of Type IA phosphatidylinositol-3-kinase (PI3K) signalling plays a critical role in both cancer and insulin resistance (IR). Yet how specificity of biological response to diverse stimuli is achieved by PI3K, and how this is perturbed in IR and related growth disorders, is not fully understood, in part because both knockout and transgenic overexpression of PI3K components perturb the stoichiometry of regulatory and catalytic subunits. Activating somatic PI3K mutations are commonly implicated in cancer pathogenesis, but have not been studied in isolation in human cells, while no unequivocal loss of function mutations in PI3K have been described to date. This project builds on recent work in the host laboratory on genetic disorders of AKT signalling by focussing on patients with rare functional mutations in the p110 catalytic subunit of PI3K, two in patients with severe IR, and one in mosaic form in a patient with unrestrained leg overgrowth. The project comprises compreh ensive genetic work up of these findings, metabolic study of the patients and relevant tissues, and signalling studies in dermal fibroblasts available for each patient exploiting state-of-the art techniques and a new collaboration, and permitting cell-based screening of potential therapeutic efficacy of a variety of pharmacological and genetic manipulations.
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Grant Details
Amount Awarded | 212922 |
Applicant Surname | Parker |
Approval Committee | Clinical Interview Committee |
Award Date | 2011-12-08T00:00:00+00:00 |
Financial Year | 2011/12 |
Grant Programme: Title | Research Training Fellowship |
Internal ID | 097721/Z/11/Z |
Lead Applicant | Dr Victoria Parker |
Partnership Value | 212922 |
Planned Dates: End Date | 2015-02-05T00:00:00+00:00 |
Planned Dates: Start Date | 2012-02-06T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |
Sponsor(s) | Prof Sir Stephen O'Rahilly |