Kari Østerli - Uncovering the molecular basis for nutritional reprogramming of pancreatic cells using novel in situ and genome wide approaches
The endocrine pancreas plays a key role in regulating the nutrient uptake and metabolism. The pancreatic β-cells respond to nutrients in the blood by increasing the insulin secretion, which in turn increases the storage of nutrients.
Type 2 diabetes is caused by malfunctioning of this regulatory circuit and inability of the β-cells to secrete sufficient amounts of insulin to meet the demands for nutrient storage. It is believed that nutrients act both to promote adaptation of β-cells to higher demands of insulin as well as stressors that can lead to dysfunction. However, so far the adaptive and pathogenic changes in β-cell gene expression and the mechanism that lead to these are far from understood.
The primary aim for the PhD project is to characterize and understand the mechanisms underlying the genomic reprogramming of β-cells in response to nutrients. The proposed project will exploit three different systems to maximize the generation of novel insight. The rat insulinoma βcell model, INS-1E, will b used to characterize transcriptional mechanisms, whereas isolated islets of Langerhans will be used to validate function of transcription factors. The novel creTRAP system will be used to profile transcriptional responses to nutritional challenges in vivo and to investigate the role of the identified regulators in vivo.
Finally, human islets will be used to investigate if the transcription factors identified as key mediators of the adaptive and pathogenic changes in rodent islets are also expressed and important for the transcriptional response to nutritional challenges in human β-cell measured by transcriptomic profiling in loss-of-function studies. Thus, this project is important for the understanding of the pleiotropic effects of hyperglycemia on β-cells, especially in context of proliferation and glucose-stimulated insulin secretion.