The primary objective of the Institute of Diabetes and Regeneration Research (IDR) is to develop regenerative therapeutic approaches to treat diabetes mellitus. We provide an international environment and stimulating atmosphere in an institute dealing with various aspects of beta cell biology.
Diabetes mellitus is a complex and multifactorial disease characterized by progressive loss or dysfunction of the insulin-producing beta cells in the pancreas. Up to now, no treatments can stop or reverse the progression of the disease except bariatric surgery and islet transplantation1. Therefore, novel therapies need to be developed to protect or regenerate functional beta cell mass. Promising new approaches include triggering endogenous beta cell regeneration by i.e. stimulating beta cell replication and replacing lost cells by human pluripotent stem cell-derived beta cells2. The early postnatal phase of life is critical for the establishment of the functional beta cell mass as i) beta cells are newly formed by neogenesis from progenitors and replication, ii) beta cells functionally mature and iii) beta cell heterogeneity is established3. From studies in rodents, it is known that functional maturation of beta cells is accompanied by changes in beta cell metabolism i.e. amino acid deprivation and decreased ROS production, by morphogenetic (new niche signals) and dietary changes. However, the translation of rodent research into human islet (patho)physiology is not straight forward due to species differences preventing the development of new therapies. Pig is a large animal model with a long lifespan that shares physiological similarities to human, and is thus a better model system for clinical translation compared to rodent animal models1.
Deciphering mechanisms of pancreatic beta cell formation in a large animal model
In this project, we will use pig models (in collaboration with E. Wolf, LMU Munich) to decipher the mechanisms that govern beta cell mass expansion and beta cell maturation during the early postnatal phase to identify targets for new therapeutic approaches.
In a collaboration with the MacDonald lab at the Alberta Diabetes Institute we will compare postnatal human and pig islets.
The proposed project aims to:
i) define the spatiotemporal transcriptional and morphogenetic dynamics of porcine pancreatic islet cells.
ii) reconstruct a trajectory for beta cell maturation to reveal maturation-associated changes in gene expression.
iii) dissect cell-cell interactions in the islet that potentially affect functional beta cell states/ beta cell heterogeneity.
The PhD candidate will work with mouse, pig and human models and employ cutting edge technologies, such as single-cell RNA/ATAC sequencing, spatial transcriptomics, bioinformatics (in collaboration with F. Theis, ICB, HMGU), 3D organoids, high-resolution imaging, CRISPR/Cas9 genome editing and phenotype analysis in vitro and in vivo.
- Bakhti, M., Böttcher, A. & Lickert, H. Modelling the endocrine pancreas in health and disease. Nature Reviews Endocrinology (2019)doi:10.1038/s41574-018-0132-z.
- Tritschler, S., Theis, F. J., Lickert, H. & Böttcher, A. Systematic single-cell analysis provides new insights into heterogeneity and plasticity of the pancreas. Molecular Metabolism (2017) doi:10.1016/j.molmet.2017.06.021.
- Roscioni, S. S., Migliorini, A., Gegg, M. & Lickert, H. Impact of islet architecture on β-cell heterogeneity, plasticity and function. Nature Reviews Endocrinology (2016) doi:10.1038/nrendo.2016.147.