erlenmyer-research
Research group/lab

Novel therapies for cystic fibrosis, diarrheal diseases and metabolic syndrome

In our lab we aim to develop drug-based therapies against disorders of intestinal electrolyte and nutrient transport, using transgenic mice and human intestinal epithelial organoids (“mini-organs”) as models

About our research group/lab

Our research

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 cultured “mini-guts” (organoids).

Novel therapies for cystic fibrosis and IBS-C 
Cystic fibrosis (CF) is caused by mutations in the CF gene encoding a  tightly regulated epithelial chloride/bicarbonate channel (CFTR). Luminal dehydration, mucus plugging and obstruction are hallmarks of CF gastrointestinal disease, and may also be found in IBS-C. This project aims to correct luminal dehydration and to prevent intestinal obstruction in CF and IBS-C through stimulation of the guanylin-cyclic GMP signaling axis. Agonists of this pathway are tested for their ability to inhibit sodium and fluid absorption and to prevent intestinal obstruction  in various model systems, including intestinal organoids cultured from CF patients.

Novel therapies for metabolic syndrome (obesitas)
Metabolic syndrome, which is associated with obesity, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM) and cardiovascular disease, is a leading cause of morbidity and mortality in Western society. Central to these metabolically driven pathologies are an excessive caloric intake, and a dysregulation of insulin secretion and blood glucose levels. Novel therapeutic strategies focus on the well-established glucose-lowering effect of the incretin family of gut-derived peptides, but the efficacy and application of incretin mimetic drugs is limited. We explore a different strategy to control blood glucose levels and satiety in the context of metabolic syndrome, directed at enhancing the production of  endogenous incretins. 
 

Key Publications

1. De Jonge HR. Cyclic nucleotide dependent phosphorylation of intestinal epithelial proteins. Nature 262, 590 593, 1976
2. Bijman, J., De Jonge, H.R. and Wine, J.  Cystic Fibrosis advantage. Nature 336: 430, 1988
3. Veeze, H.J., Sinaasappel, M., Bijman, J., Bouquet, J. and De Jonge, H.R. Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis. Gastroenterology 101: 398-403, 1991
4. Vaandrager, A.B., Van der Wiel, E. and De Jonge, H.R. Heat-stable enterotoxin activation of immunopurified guanylyl cyclase C. J. Biol. Chem. 268: 19598-19603, 1993
5. Veeze, H.J., Halley, D.J.J., Bijman, J., De Jongste, J.C., De Jonge, H.R. and Sinaasappel, M. Determinants of mild clinical symptoms in cystic fibrosis patients. J. Clin. Invest. 93: 461-466, 1994
6. Vaandrager,  A.B., Tilly, B.C., Smolenski, A., Schneider-Rasp, A., Bot, A.G.M., Edixhoven, M.J., Scholte, B.J., Jarchau, T., Walter, U., Lohmann, S.M., Poller, W.C. and De Jonge, H.R. cGMP stimulation of cystic fibrosis transmembrane conductance regulator Cl- channels co-expressed with cGMP-dependent protein kinase type II but not type Iß. J. Biol. Chem. 272: 4195-4200, 1997
7. Lohmann, S.M., Vaandrager, A.B., Smolenski, A., Walter, U. and De Jonge, H.R. Distinct and specific functions of cGMP-dependent protein kinases. Trends Biochem. Sci. 22: 307-312, 1997
8. Vaandrager, A.B., Bot, A.G.M., Ruth, P., Pfeifer, A., Hofmann, F, and De   Jonge, H.R. Abnormalities in intestinal ion transport in mice lacking  guanosine 3’,5’-cyclic monophosphate-dependent protein kinase II. Gastroenterology 118: 108-114, 2000
9. Verloo, P., Kocken, C.H., Van der Wel, A., Tilly, B.C., Hogema, B.M., Sinaasappel, M., Thomas, A.W., and De Jonge, H.R. Plasmodium falciparum-activated chloride channels are defective in 
erythrocytes from cystic fibrosis patients. J. Biol. Chem. 279: 10316-10322, 2004
10. Scholte, B.J., Davidson, D.J., Wilke, M., and De Jonge, H.R. Animal models of cystic fibrosis. J Cystic Fibrosis 3: 183-190, 2004
11. Kleizen, B., Van Vlijmen, T., De Jonge, H.R., and Braakman, I. Folding of CFTR is predominantly cotranslational. Mol. Cell 20: 277-287, 2005
12. Vaandrager, A.B., Hogema, B.M., and De Jonge, H.R. Molecular properties and biological functions of cGMP-dependent protein kinase II. Front Biosci. 10:2150-2164, 2005
13. Bijvelds MJ, Bot AG, Escher JC, de Jonge HR. Activation of intestinal Cl- secretion by lubiprostone requires the Cystic Fibrosis Transmembrane conductance Regulator.  Gastroenterology 137: 976-985, 2009
14.Wilke M, Bot A, Jorna H, Scholte BJ, De Jonge HR. Rescue of murine F508del CFTR activity in native intestine by low temperature and proteasome inhibitors. PLoS One 7: e52070, 2012
15. Dekkers JF, Wiegerinck CL, De Jonge HR, Bronsveld I, Janssens HM, De Winter-De Groot KM, Bijvelds MJC, Nieuwenhuis EES, Van den Brink S, Clevers H, Van der Ent CK, Middendorp S, Beekman JM. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nature Med 19: 939-945, 2013 
16. Ikpa PT, Bijvelds MC, De Jonge HR. Cystic fibrosis: toward personalized therapies. Intl J Biochem Cell Biol 52:192-200, 2014
17. Bijvelds MJ, Loos M, Bronsveld I, Hellemans A, Bongartz JP, Ver Donck L, Cox E, de Jonge HR, Schuurkes JA, De Maeyer JH. Inhibition of heat-stable toxin-induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors. J Infect Dis 212:1806-15, 2015
18. Foulke-Abel J, In J, Yin J, Zachos NC, Kovbasnjuk O, Estes MK, de Jonge H, Donowitz M. Human enteroids as a model of upper small intestinal ion transport physiology and pathophysiology. Gastroenterology 150:638-649, 2016
19. Dekkers JF, van Mourik P, Vonk AM, Kruisselbrink E, Berkers G, de Winter-de Groot KM, Janssens HM, Bronsveld I, van der Ent CK, Beekman JM, De Jonge HR.  Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations. J Cyst Fibros 15(5):568-578, 2016
20. Bijvelds MJC, Tresadern G, Hellemans A, Smans K, Nieuwenhuijze NDA, Meijsen KF, Bongartz JP, Ver Donck L, de Jonge HR, Schuurkes JAJ, De Maeyer JH. Selective inhibition of intestinal guanosine 3',5'-cyclic monophosphate signaling by small-molecule protein kinase inhibitors. J Biol Chem 293: 8173-8181, 2018
21. Bose SJ, Bijvelds MJC, Wang Y, Liu J, Cai Z, Bot AGM, de Jonge HR, Sheppard DN. Differential thermostability and response to cystic fibrosis transmembrane conductance regulator (CFTR) potentiators of human and mouse F508del-CFTR. Am J Physiol Lung Cell Mol Physiol. 2019 Apr 10. doi: 10.1152/ajplung.00034, 2019.
 

Collaborations

Collaboration within Erasmus MC

  • Erasmus Optical Imaging Center, Department of Pathology
  • Laboratorium, Afdeling Heelkunde
  • Centraal Klinisch laboratorium
  • Afdeling Kindergeneeskunde, SKZ

Collaboration outside of Erasmus MC

Prof. Mark Donowitz, Johns Hopkins Medical Center, Baltimore, USA
Prof. Ray Frizzell, University of Pittsburgh, USA
Prof. David Sheppard, University of Bristol, UK
Prof. Ursula Seidler, Hannover Medical School, Germany
Prof. Isabelle Sermet-Gaudelus, Hospital Necker-Enfants Malades, Paris, France
Prof. Zoya Ignatova, University of Hamburg, Germany
Dr. Claudio Sorio/Paola Melotti, University of Verona, Verona, Italy
Prof. Ineke Braakman, Department of Cellular Protein Chemistry, Utrecht University, Utrecht, Netherlands
Dr. Jeffrey Beekman, Utrecht University Medical Center/Hubrecht Institute, Utrecht, Netherlands

 

Funding & Grants

2016-2018 Grant CFF-USA: Bicarbonate transport studies in 2D and 3D intestinal organoids from healthy controls and CF patients; 1 postdoc; $210.000,-
2017-2019 Grant Van der Vorm Foundation, Monaco: Bicarbonate transport defects in CF organoids; 1 technician; $160.000,-
2017-2020: SRC grant UK CF Trust: Restoration of luminal fluidity and microbiota in the CF gut (CFGI-SRC); 1 postdoc; £203.340,-
2019: Grant NCFS HIT-CF2: Repair of bicarbonate transport across CFTR channels; € 50.000,-
2019-2021: Grant CFF-USA: Repair of the cystic fibrosis defect in intestinal guanylin signalling; 1 research scientist; $230.000,-
2019-2021: Grant Van der Vorm Foundation, Monaco: Guanylin signalling in epithelial tissues; 1 technician; €150.000,-
2019-2022: Grant AlgiPharma, Norway: Use of Oligo-G and nanoparticles to dissolve CF mucus. €240.000,-
2019-2020: Mrace grant ErasmusMC: Stimulation of incretin production by the intestinal guanosine 3’,5’-cyclic monophosphate signaling axis: a novel paradigm for treatment of hyperglycemia; 1 technician; €50.000,-
 

Our team

Hugo de Jonge-Associate Professor/Group Leader, h.dejonge@erasmusmc.nl

Marcel Bijvelds-Senior Research Scientist, m.bijvelds@erasmusmc.nl

Pauline Ikpa-Post-doc, p.ikpa@erasmusmc.nl

Kelly Meijsen, Research Technician, k.meijsen@erasmusmc.nl

Natascha Nieuwenhuijze, Research Technician, n.nieuwenhuijze@erasmusmc.nl