Investigating neural fine-tuning of pancreatic islet physiology in health and disease (360G-Wellcome-305101_Z_23_Z)

The project will advance our understanding of neural-pancreas crosstalk by investigating peripheral neurobiology with precision on physiological time scales. Hormones from pancreatic islets are crucial for glucose homeostasis and loss of regulated insulin release leads to diabetes and its many co- morbidities. Secretion of other islet hormones is also dysregulated in diabetes. How neural input contributes to the fine-tuning of islet physiology is underexplored yet represents an opportunity to therapeutically control hormone release in diabetes. To achieve this, I will establish how peripheral nerves adapt to pathophysiological contexts by identifying molecular targets to prevent/delay diabetes progression. Critically for future therapeutic efficacy, I will study how sexual dichotomy impacts neural-pancreas interplay to better target the cellular mechanisms underlying the sex differences in disease progression. I will implement a genetic toolbox for live zebrafish analysis of pancreas physiology, neural tracing, and optogenetic control of neurons and signalling pathways to define fully the physiological roles of islet innervation for the maintenance of pancreas homeostasis in health and disease. Additionally, I will validate the translatability of my findings in primary human islets. These fundamental studies will allow us to understand how pancreatic innervation contributes to diabetes aetiology and to harness neural signalling for therapeutic means.