About our research group/lab
Our research
Pharmacological repair of CFTR function in cystic fibrosis
Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF gene, which encodes a tightly regulated epithelial chloride and bicarbonate channel, CFTR. Novel modulator drugs that improve mutant CFTR function have transformed treatment of CF, but the development of these compounds has been directed by assays monitoring changes in chloride permeation, whereas restoration of bicarbonate transport is seldom studied. We aim to increase our knowledge of CFTR-dependent bicarbonate secretion, in the hope that a better understanding of its role in the pathophysiology of the disease may ultimately improve pharmacological treatment of people with CF. Further, we aim to correct luminal dehydration and to prevent luminal obstruction in CF through stimulation of alternative pro-secretory or anti-absorptive pathways.
CFTR dysfunction in pancreatitis
Pancreatitis is a common cause of hospitalization, with a high mortality rate and with no specific therapy currently available. Mutation of CFTR increases the risk of recurrent acute or chronic pancreatitis and there is evidence to suggest that loss of CFTR function plays a role in the pathophysiology of alcohol-induced pancreatitis. In the pancreas, CFTR is expressed exclusively in the ductal epithelial cells (PDECs) and is crucial for the formation of a bicarbonate-rich secretion. Our aim is to further elucidate the molecular mechanisms involved in the disruption of CFTR function in pancreatitis and to develop new therapies based on pharmacological restoration of CFTR function.
Novel therapies for secretory diarrhea and IBS-D
The aim of this project is to identify novel small molecule compounds that can be developed into drugs for the treatment of secretory diarrhea (SD) and, possibly, inflammatory bowel disease (IBS). In addition, by studying the inflammatory mediators related to intestinal secretion, new insights will be gained into the disease mechanism, potentially leading to new discovery fields. In this project, protein kinase, guanylyl cyclase and ion channel modulators emerging from high-throughput screening assays are validated for efficacy and specificity in human rectal biopsies and in organoids.
In these projects, we use advanced stem-cell, biochemical, molecular biology and genomics-based technologies to investigate epithelial anion secretion and luminal pH regulation, and use the organoid platform to develop new methods to assess (CFTR-dependent) bicarbonate secretion in CF-affected gastro-intestinal tissues.
Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF gene, which encodes a tightly regulated epithelial chloride and bicarbonate channel, CFTR. Novel modulator drugs that improve mutant CFTR function have transformed treatment of CF, but the development of these compounds has been directed by assays monitoring changes in chloride permeation, whereas restoration of bicarbonate transport is seldom studied. We aim to increase our knowledge of CFTR-dependent bicarbonate secretion, in the hope that a better understanding of its role in the pathophysiology of the disease may ultimately improve pharmacological treatment of people with CF. Further, we aim to correct luminal dehydration and to prevent luminal obstruction in CF through stimulation of alternative pro-secretory or anti-absorptive pathways.
CFTR dysfunction in pancreatitis
Pancreatitis is a common cause of hospitalization, with a high mortality rate and with no specific therapy currently available. Mutation of CFTR increases the risk of recurrent acute or chronic pancreatitis and there is evidence to suggest that loss of CFTR function plays a role in the pathophysiology of alcohol-induced pancreatitis. In the pancreas, CFTR is expressed exclusively in the ductal epithelial cells (PDECs) and is crucial for the formation of a bicarbonate-rich secretion. Our aim is to further elucidate the molecular mechanisms involved in the disruption of CFTR function in pancreatitis and to develop new therapies based on pharmacological restoration of CFTR function.
Novel therapies for secretory diarrhea and IBS-D
The aim of this project is to identify novel small molecule compounds that can be developed into drugs for the treatment of secretory diarrhea (SD) and, possibly, inflammatory bowel disease (IBS). In addition, by studying the inflammatory mediators related to intestinal secretion, new insights will be gained into the disease mechanism, potentially leading to new discovery fields. In this project, protein kinase, guanylyl cyclase and ion channel modulators emerging from high-throughput screening assays are validated for efficacy and specificity in human rectal biopsies and in organoids.
In these projects, we use advanced stem-cell, biochemical, molecular biology and genomics-based technologies to investigate epithelial anion secretion and luminal pH regulation, and use the organoid platform to develop new methods to assess (CFTR-dependent) bicarbonate secretion in CF-affected gastro-intestinal tissues.
Key Publications
- Bijvelds MJC, Roos FJM, Meijsen KF, Roest HP, Verstegen MMA, Janssens HM, et al. Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers. J Cyst Fibros. 2022;21:537-43.
- Van Vugt AHM, Bijvelds MJC, de Jonge HR, Meijsen KF, Restin T, Bryant MB, et al. A potential treatment of congenital sodium diarrhea in patients with activating GUCY2C mutations. Clin Transl Gastroenterol. 2021;12(11):e00427.
- Angyal D, Bijvelds MJC, Bruno MJ, Peppelenbosch MP, de Jonge HR. Bicarbonate Transport in Cystic Fibrosis and Pancreatitis. Cells. 2021;11(1).
- Ikpa PT, Meijsen KF, Nieuwenhuijze NDA, Dulla K, De Jonge HR, Bijvelds MJC. Transcriptome analysis of the distal small intestine of Cftr null mice. Genomics. 2020;112(2):1139-50.
- Ikpa PT, Doktorova M, Meijsen KF, Nieuwenhuijze NDA, Verkade HJ, Jonker JW, De Jonge HR, Bijvelds MJC. Impaired intestinal farnesoid X receptor signaling in cystic fibrosis mice. Cell Mol Gastroenterol Hepatol. 2020;9(1):47-60.
- De Jonge HR, Ardelean MC, Bijvelds MJC, Vergani P. Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas. FEBS Lett. 2020;594(23):4085-108.
- Bose SJ, Bijvelds MJC, Wang Y, Liu J, Cai Z, Bot AGM, et al. Differential thermostability and response to cystic fibrosis transmembrane conductance regulator (CFTR) potentiators of human and mouse F508del-CFTR. Am J Physiol. 2019.
- Bijvelds MJC, Tresadern G, Hellemans A, Smans K, Nieuwenhuijze NDA, Meijsen KF, et al. Selective inhibition of intestinal guanosine 3',5'-cyclic monophosphate signaling by small-molecule protein kinase inhibitors. J Biol Chem. 2018;293(21):8173-81.
- Ikpa PT, Sleddens HFBM, Steinbrecher KA, Peppelenbosch MP, De Jonge HR, Smits R, Bijvelds MJC. Guanylin and uroguanylin are produced by mouse intestinal epithelial cells of columnar and secretory lineage. Histochem Cell Biol. 2016;146:445-55.
- Bijvelds MJC, Loos M, Bronsveld I, Hellemans A, Bongartz JP, Ver Donck L, et al. Inhibition of heat-stable toxin-induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors. J Infect Dis. 2015;212(11):1806-15.
- Bijvelds MJC, de Jonge HR, Verkade HJ. Bile acid handling in cystic fibrosis: marked phenotypic differences between mouse models. Gastroenterology. 2012;143(6):e19-20.
- Bijvelds MJC, Bot AG, Escher JC, De Jonge HR. Activation of intestinal Cl- secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator. Gastroenterology. 2009;137(3):976-85.
- Bijvelds MJC, Jorna H, Verkade HJ, Bot AGM, Hofmann F, Agellon LB, et al. Activation of CFTR by ASBT-mediated bile salt absorption. Am J Physiol. 2005;289:G870-G9.
Collaborations
Collaboration within Erasmus MC
- Optical Imaging Center
- Department of Surgery
- Department of Pediatrics
Collaboration outside of Erasmus MC
- Prof. Jeffrey Beekman, University Medical Center, Utrecht, Netherlands
- Prof. Ineke Braakman, Utrecht University, Utrecht, Netherlands
- Prof. Mark Donowitz, Johns Hopkins Medical Center, Baltimore, USA
- Dr. Paola Melotti, University of Verona, Verona, Italy
- Prof. Ursula Seidler, Hannover Medical School, Germany
- Prof. Isabelle Sermet-Gaudelus, Institut Necker Enfants Malades, Paris, France
- Prof. David Sheppard, University of Bristol, UK
- Soraya P Shirazi-Beechey, University of Liverpool, UK
- Dr. Claudio Sorio, University of Verona, Verona, Italy
- Dr. Paola Vergani, University College London, UK
- Prof. Sandhya S. Visweswariah, Indian Institute of Science, Bangalore, India
Funding & Grants
- 2019-2022: CFF, USA. Repair of the cystic fibrosis defect in intestinal guanylin signaling. $230.000,-
- 2019-2022: AlgiPharma, Norway. Novel alginate oligomer products for enhanced delivery across mucosal barriers. €100.000
- 2020-2022: Erasmus MC MRace. Stimulation of incretin production by the intestinal guanosine 3’,5’-cyclic monophosphate signaling axis: a novel paradigm for treatment of hyperglycemia. €50.000,-
- 2021-2023: Van der Vorm Foundation, Monaco. Guanylin signaling in epithelial tissues. €150.000,-
- 2023-2026: UK CF Trust. Restoring the Fizz: Pharmacological Repair of Bicarbonate Transport in Cystic Fibrosis. € 190.000,-
- 2023-2026: NCFS HIT-CF3. Repair of bicarbonate transport in CF. € 90.000,-
- 2023-2026: NCFS HIT-CF3. Preclinical testing of anti-constipation drugs for CF intestinal and lung disease. € 130.000,-
Our team
Dora Angyal, PhD student
d.angyal@erasmusmc.nl
Anny Leung, Research Technician
a.leung@erasmusmc.nl
Tessa Groeneweg, Research Technician
t.groeneweg@erasmusmc.nl
d.angyal@erasmusmc.nl
Anny Leung, Research Technician
a.leung@erasmusmc.nl
Tessa Groeneweg, Research Technician
t.groeneweg@erasmusmc.nl
