Project name: Project category: Kind of research: Country: Principle investigator:

Bicarbonate transport in human intestinal biopsies and organoids (CF/nonCF)

Cell Biology
Physiology
Basic research Netherlands Prof. Hugo de Jonge
Start date: 2017
End date: 2021
Status: Ongoing
Abstract:

Accumulation of viscid mucus in the lung, intestine, pancreas, hepatobiliary tract, and reproductive tract is a hallmark of cystic fibrosis (CF) and is the primary cause of defective mucociliary clearance in the airways and of luminal obstruction in the intestine and reproductive tract. Recent studies in CF animal models (mouse, pig, rat) indicate that normal mucus release in intestinal and airway epithelium requires concurrent bicarbonate (“soda”) secretion and that, in the absence of bicarbonate, mucins released by goblet cells remain densily packed and attached to the epithelial surface (“mucoviscoidosis”). Bicarbonate can be transported directly by the CF-gene encoded molecular chloride channel (“CFTR”), or indirectly by chloride/bicarbonate exchangers that are functionally or physically coupled to CFTR. However, in contrast to the wealth of information about the chloride transport defect in epithelia from both CF mice and CF patients, there is as yet a paucity of data about bicarbonate secretion and mucus release in epithelia from both healthy individuals and CF patients. Here we aim to fill this knowledge gap by studying features of bicarbonate transport in a readily accessible tissue, i.e. rectal biopsies and 3D and 2D cultures of rectal organoids (‘mini-guts’) generated from intestinal stem cells, obtained from healthy controls and CF patients. The study will reveal whether CFTR targeting drugs, known to restore its Cl- channel function (e.g. ivacaftor and lumacaftor), are also able to restore its bicarbonate transport function. The protocols developed may facilitate future preclinical testing of novel CFTR repair molecules for their ability to restore bicarbonate transport in rectal biopsies and organoids generated from CF individuals (“personalized medicine”). Considering the close functional similarities between bicarbonate secretion by intestinal crypts and submucosal glands in the airways, the results may be of relevance too for CF lung disease.

Website URL: https://www.ncfs.nl/onderzoek/lopend/hitcf
Researcher: Dr. Marcel Bijvelds
Institute: Erasmus MC
City: Rotterdam
Project amount (€): 50.000

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