Title: Secrets of secretion: the role of Klu-targets in entero-endocrine cell differentiation in flies and humans
Funder: The Academy of Medical Sciences

Abstract: This project aims to understand how entero-endocrine (EE) cells in the intestine are generated from stem cells using a combination of Drosophila genetics and organoid culture. Hormones play a pivotal role in controlling and monitoring our health status by facilitating communication locally and between distant organs. Hormone-producing EE cells in the intestine together form the largest endocrine organ in the body and signals about nutritional status and satiety to distant organs such as the brain, muscle or liver. Deregulation of hormone signaling leads to obesity and diabetes, two of the most prevalent diseases with health-care costs of diabetes being over 2 billion £/year in the UK alone. Our previous work has identified the transcription factor Klumpfuss (Klu) as a key negative regulator of EE differentiation. We will test a set of high-confidence Klu target genes for their role in EE differentiation and function. Our preliminary data shows that the CG9650/Bcl11B gene is both a high-confidence Klu-target and localized to EEs as well. We will study CG9650 and other Klu-targets for their effect on EE differentiation by knockdown and overexpression in the Drosophila intestine well as in human intestinal organoids using CRISPR-Cas9-mediated knockout organoids. The strength of each model will allow us to better study the different aspects of EE function, such as inter-organ communication (Drosophila) as well as paracrine effects and pharmaceutical interventions (organoid culture). This two-species approach will help identify novel and conserved pathways in entero-endocrine differentiation that could help identify novel strategies to treat metabolic diseases.

Lay abstract: The cells in our body are in constant communication with each other. They send and receive signals about their energy level, stress and infections between organs widely apart. Our intestine is the major centre for the processing of the food we eat. It relays information about our nutrition and energy levels to distant parts of our body such as the brain or the muscle. To do this, the intestine produces hormones that relay these signals to distant organs. The cells producing these hormones are called entero-endocrine or EE cells. As an imbalance in hormone signaling is one of the leading causes of diseases such as obesity and diabetes, it is of crucial importance to understand how these cells are generated and how they function. Like our human intestine, the intestine of the fruit fly contains entero-endocrine cells that function in a similar way. The short lifespan and our deep knowledge of this organism makes it a useful subject to study EE cell differentiation. We found a gene called Klumpfuss (Klu) that functions as an OFF-switch for EE cell generation. Based on this, we identified many factors regulated by Klu that likely play a role in the generation of EEs. With this proposal, we will test these factors for their effect on EE cell generation and function in both the fruit fly intestine as well as human mini-gut “organoids” to see if these factors could possibly help us develop cures for diseases such as diabetes and obesity.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE