Investigation of Metabolic and Growth-related Diseases Associated with Mutations in Phosphoinositide-3-kinase, Catalytic, Alpha Polypeptide (PIK3CA). (360G-Wellcome-097721_Z_11_Z)

£212,922

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