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Understanding the Biology of Human Enteroendocrine Cells

Project description

Insight into hormone-secreting cells of the intestine

The intestinal epithelium forms a dynamic lining of the digestive system. Among other cell types, the epithelium contains enteroendocrine cells (EECs) that regulate gastrointestinal activity, metabolism, and food intake through the secretion of hormones. The scope of the EU-funded GutHormones project is to study the biology and triggers of EECs using gut organoids engineered to contain all EEC lineages. Researchers will investigate how the different lineages interact with each other as well as their sensing function. Complete characterisation of this cell type will open new possibilities for therapeutic interventions against metabolic diseases, such as diabetes and obesity.

Objective

Intestinal epithelium consists of self-renewing crypt-villus units and contains 6 mature cell types: Enterocytes, goblet cells, Paneth cells, Tuft cells, M cells and Enteroendocrine cells (EECs). The rare EECs are subclassified by the (>20) hormones they produce. Generally, EECs sense intestinal content and regulate gastrointestinal activity, systemic metabolism and food intake. While one EEC hormone, GLP1, has been developed into a highly successful diabetes drug, a paucity of laboratory models has complicated human EEC studies.
Previously, we identified adult crypt stem cells by the novel marker Lgr5, and established conditions to grow ‘gut organoids’ from these. By single cell RNA sequencing, we have resolved the complex EEC subtype hierarchy into 5 lineages. Our studies underscore significant differences between mouse and man, not unexpected given the divergent diets and metabolism. Gut organoids can be manipulated to contain all EEC lineages. We have created a set of human organoids in which the individual hormones are fluorescently tagged by CRISPR.
The current proposal exploits the technologies described above, as well as our ‘Human EEC Atlas’ to generate a detailed picture of the biology of EECs, their triggers, their interconnectivity and their products. To this end, I propose to:
1. Complete the Human EEC Atlas and hormone-tagged organoid set for stomach and colon.
2. Resolve how individual EEC subtype fates are set.
3. Resolve which luminal receptors and ligands allow sensing of nutrient components and microbial products
4. Resolve cross-regulation of EEC subtypes.
5. Investigate systemic effects of novel EEC products in mouse knockout models.
Successful completion of this proposal will generate a comprehensive characterisation of EECs. This will inspire new therapeutic approaches to reshape the EEC landscape for treatment of metabolic diseases (obesity, diabetes, fatty liver disease, atherosclerosis) and other consequences of the Western-type diet.

Host institution

F. HOFFMANN-LA ROCHE AG
Net EU contribution
€ 870 285,31
Address
GRENZACHERSTRASSE 124
4070 Basel
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Links
Total cost
€ 870 285,31

Beneficiaries (2)