Targeting the gut in metabolic disease (360G-Wellcome-220271_Z_20_Z)
This project aims to identify new strategies to target the gut for the treatment of type 2 diabetes and obesity. Intestinal hormones regulate intestinal nutrient absorption, insulin secretion and appetite, and therapeutics based on the gut peptide GLP-1 are widely used for type 2 diabetes and obesity. Bariatric surgery causes weight loss and resolves diabetes at least in part via gut endocrine changes. This project will characterise human enteroendocrine cells using intestinal organoid cultures, building on our previous work using transgenic mouse models. To identify cells of interest, organoids will be engineered by CRISPR/Cas9 to express fluorescent sensors driven by hormonal promoters, allowing cellular analysis by transcriptomics, electrophysiology and real-time fluorescence imaging of e.g. Ca2+ and cAMP. We will characterize nutrient sensing pathways and identify receptors and signaling pathways potentially modifiable therapeutically. Using mouse and human tissues, we will identify circuitry involved in bidirectional cross-talk between gut endocrine cells and enteric/autonomic nerves. Building on our new methods to analyse peptides and the low molecular weight proteome by mass-spectrometry, we will investigate how plasma peptides respond to nutrient ingestion in health and metabolic diseases including diabetes, obesity, lipodystrophy and anorexia nervosa, and following bariatric surgery or dietary calorie restriction in obesity.
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Grant Details
Amount Awarded | 2381203 |
Applicant Surname | Gribble |
Approval Committee | Science Interview Panel |
Award Date | 2020-03-31T00:00:00+00:00 |
Financial Year | 2019/20 |
Grant Programme: Title | Investigator Award in Science |
Internal ID | 220271/Z/20/Z |
Lead Applicant | Prof Fiona Gribble |
Other Applicant(s) | Prof Frank Reimann |
Partnership Value | 2381203 |
Planned Dates: End Date | 2026-03-31T00:00:00+00:00 |
Planned Dates: Start Date | 2021-04-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |