G protein-coupled receptors (GPCR) represent the largest family among membrane receptors. They play a major role in a variety of physiological and pathophysiological processes and constitute the targets for 30% of the active compounds presently used as therapeutic agents. Our objective is to study new paradigms in activation, signalling and regulation of GPCRs and determine their contribution in pathophysiological processes using mice models.
The experimental approach involves cell and molecular biology, pharmacology, organoid culture technology and in vivo studies.
Unravelling the multifaceted role of the VIP pathway in homeostasis and diseases of the colonic mucosa.
Supervisor: Dr. Ingrid Langer
Vasoactive Intestinal Polypeptide (VIP) and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) are two neuropeptides that regulate many physiological functions such as development, growth, circadian rhythms, smooth muscles tone, endocrine and exocrine secretions. Their effects are mediated through the interaction with three GPCRs widely expressed in the body: VPAC1, VPAC2 and PAC1. In the intestine, VIP, through VPAC1, regulates secretions of water and electrolytes as well as contractions of the intestinal smooth muscles. VIP also regulates the development and the homeostasis of the intestinal barrier. As well, VIP and PACAP have been implicated in the regulation of immune response and carcinogenesis1,2.
Chronic gut diseases and cancers are typically multifactorial, including dysfunction and dysregulated communication between different cell compartments3,4. Therefore, understanding of signalling pathways and microenvironmental regulations that orchestrate homeostatic and pathologic conditions in epithelial tissue is a key milestone for new diagnostics and therapeutics discovery, and ultimately satisfy unmet medical need.
The main objective of our project is to unravel the intricate molecular mechanisms underlying the multifaceted role of the VIP pathway in both the homeostasis and disease states of the colonic mucosa by using adult stem cell (ASC)-derived organoids as disease models. We aim to characterize the precise contribution of the different actors of the VIP pathway both at the epithelial and the mesenchymal cell level by combining transcriptomic and proteomic approaches.
All together, we anticipate that our results will: 1) Allow better understanding of the contribution of VIP/PACAP in IBD and colorectal cancer, shedding light on critical aspects of the pathogenesis of these diseases; 2) Deliver new in vitro models to test drug candidates.
- Langer I et al. Signal Transduction by VIP and PACAP Receptors. Biomedicines. 2022 Feb 9;10(2):406.
- Iwasaki M et al. Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system. F1000Res. 2019; 12:8.
- Neurath MF. Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol. 2017 14, 269–278.
- Pandurangan AK et al. Colorectal carcinogenesis: Insights into the cell death and signal transduction pathways: A review. World J Gastrointest Oncol. 2018; 10(9): 244-259