CHANGES IN VASOACTIVE INTESTINAL PEPTIDE (VIP) AMOUNT IN CYSTIC FIBROSIS

Abstract

Cystic Fibrosis (CF) is the most common lethal genetic disease in Caucasians, which results from mutations in the CFTR gene. Cystic Fibrosis - Related Diabetes (CFRD) affects more than 50% of adults with CF. The complex etiology of CFRD is poorly understood and differs from type 1 or type 2 diabetes. The major physiological agonist of the CFTR chloride channel is the Vasoactive Intestinal Peptide (VIP), a 28-amino acid neuropeptide that functions as a neuromodulator and neurotransmitter secreted by intrinsic neurons innervating exocrine glands. VIP has also insulinotropic effects on pancreatic beta cells, augmenting glucose-dependent insulin secretion. Previous studies from our lab have demonstrated the molecular role of VIP in CFTR regulation, both in vivo and in vitro. Interestingly, exocrine glands from CF patients have sparse VIPergic innervation compared to healthy individuals, but the mechanism behind this phenomenon remains unknown. The main goal of my PhD research was to investigate changes in VIP content in exocrine tissues in F508del/F508del mice, and determine if VIP depletion was related to CF disease progression. Furthermore, we examined the mechanism of this reduction in neuronal level. Lastly, we asked if the decreased VIP amount in the pancreas could contribute to CFRD pathophysiology. Our data showed a significant decrease in the VIP content throughout all exocrine tissues that was not linked to inflammation and/or to disease progression but was rather an early onset of CF disease. This VIP reduction was due to a disruption of the intrinsic innervation network. Importantly, nerves co-expressing VIP and Acetylcholine were reduced in density. In the pancreas, we found low levels of VIP due to reduced pancreatic innervation, starting at an early disease stage, which may initiate the development of CFRD through down-regulation of insulin and glucagon secretion. While most of the research is centered on how to cure the basic CFTR defects, the link of the dysfunctional nervous system to the disease progression is yet a thirst for knowledge. Our pioneer data provide fundamental knowledge to boost our understanding on neuronal alterations in CF and how this can affect the pathophysiology of CF and CFRD.