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Researcher

H.R. de Jonge, PhD

Principal Investigator

  • Department
  • Gastroenterology and Hepatology
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About

Introduction

A major present research goal of my group is the in vivo rescue of mutant-CFTR function in cystic fibrosis (CF) mice by pharmacological approaches, and the ex vivo testing of new candidate drugs (small molecule CFTR correctors and potentiators) by bioelectric and fluid transport assays in 3D and 2D cultures of GI organoids (“mini-organs”) generated from the intestine, liver and pancreas of CF patients. In addition, new approaches are explored to prevent excessive salt-and water loss in diarrheal diseases and diarrhea-predominant irritable bowel syndrome (IBS-D) by interfering with transmembrane signaling by microbial enterotoxins and endogenous secretagogues, in particular guanylin and uroguanylin. Conversely, pharmacological activators of the guanylin /guanylylcyclase /cyclicGMP signalling pathway are tested for their ability to restore luminal fluidity and intestinal motility in CF and in constipation-predominant IBS (IBS-C). Human and mouse GI organoids are exploited additionally to study CF-specific changes in gene expression (Ingenuity pathway analysis), bile salt/FXR signalling and the intestinal microbiome.

Field(s) of expertise

  • signal transduction mechanisms, in particular cyclic GMP signalling
  • regulation of epithelial ion channels, in particular chloride channels (CFTR; ClCs; volume-regulated channels), sodium channels (ENACs), and calcium channels
  • regulation of epithelial sodium/proton (NHEs) and anion exchangers (e.g. DRA)
  • pathophysiology and pharmacotherapy of chloride channel diseases: cystic fibrosis; secretory diarrhoea (mechanism of action of microbial enterotoxins, e.g. choleratoxin and the E. coli toxins STa and LT)
  • cell volume regulation: signal transduction and ion channels involved
  • stem cell biology, focussing on organoids (“mini-organs”) from CF-relevant epithelial tissues (intestine, airways).

Education and career

I received my MSc (cum laude) in Biochemistry at the Free University in Amsterdam and my PhD at the Erasmus University in Rotterdam, The Netherlands (1976) where I studied signal transduction by cyclic nucleotides and mitochondrial protein synthesis in intestinal epithelium. Following a postdoctoral training with Prof. Ohra Rosen at the Department of Pharmacology, Albert Einstein College of Medicine, New York and an EMBO Fellowship with Prof. Shmuel Shaltiel at the Department of Chemical Immunology, Weizmann Institute, Rehovot, Israel, I became an (associate) professor at the Department of Biochemistry and, from 2010 on, at the Department of Gastroenterology & Hepatology of the Erasmus University Medical Center in Rotterdam. I also served as a visiting professor at the Columbia University in New york (GI Reseach Department; head: Prof. Michael Field), the University of Alberta in Edmonton (GI Department; head: Prof. Alan Thomson), and the University of Krasnoyarsk, Russia. During my research on mechanism of ion transport regulation in epithelial cells and the molecular basis of chloride channelopathies such as secretory diarrhea (SD) and cystic fibrosis (CF), I discovered, cloned and characterized the key signaling enzymes (guanylyl cyclase, cyclic GMP-dependent protein kinase type II) involved in enterotoxin-induced diarrheal disease and identified their main molecular target, the CFTR choride channel.

So far I have published over 230 full papers in peer-reviewed international journals. I acted as a (co-) organizer and/or keynote, symposium, or workshop speaker at over 81 international conferences. I have been a recipient of many prestigious awards including the Dutch Steven Hoogendijk Award (1999) and served as an Editor of the Biochemical Journal (1987-1995), Biochemical Biophysica Acta (2002-2007), the J. Cystic Fibrosis (2000-present), and Physiological Reports (2013-present). He also served as the treasurer of the Board of the Dutch Biochemical Society (NVBMB: 1998-2007) and as a member of numerous scientific advisory boards, including the Cellular Physiology Study Section of the Neherlands Organization for the Advancement of Pure Research (NWO-ZON) (1983-1988; 1991; 1995-1996), the Dutch Foundation for Bio-Sciences (NWO-ALW) (1998-2008), the Flemish Science Organization (FWO section Medical Biochemistry) (2001-2009), and the Evaluation Panel Rare Diseases (7th Framework Programme, EU) (2007). From 2018 on I acted as the founder and director of the Applications in Organoid Technology Course at the Mount Desert Island Biological Lab (MDIBL) in Maine, USA. 

 

 

Publications

2013-present (out of 238 since 1973):
1. 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
2. Sultan A, Luo M, Yu Q, Riederer B, Xia W, Chen M, Lissner S, Gessner JE, Donowitz M, Yun CC, de Jonge H, Lamprecht G, Seidler U. Differential association of the Na+/H+ exchanger regulatory factor (NHERF) family of adaptor proteins with the Raft-and the non-raft brush border membrane fractions of NHE3. Cell Physiol Biochem 32: 1386-1402, 2013
3. Kovbasnjuk O, Zachos NC, In J, Foulke-3. Abel J, Ettayebi K, Hyser JM, Broughman JR, Zeng XL, Middendorp S, de Jonge HR, Estes MK, Donowitz M. Human enteroids: preclinical models of non-inflammatory diarrhea. Stem Cell Res Ther 4 Suppl 1:S3, 2013
4. Fisher JT, Tyler SR, Zhang Y, Lee BJ, Liu X, Sun X, Sui H, Liang B, Luo M, Xie W, Yi Y, Zhou W, Song Y, Keiser N, Wang K, de Jonge HR, Engelhardt JF. Bioelectric characterization of epithelia from neonatal CFTR knockout ferrets. Am J Respir Cell Mol Biol 49: 837-844, 2013
5. Rohof WO, Bennink RJ, de Jonge H, Boeckxstaens GE. Increased proximal reflux in a hypersensitive esophagus might explain symptoms resistant to proton pump inhibitors in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 12:1647-55, 2014 
6. De Jonge HR, Tilly BC, Hogema BM, Pfau D, Kelly CA, Kelly M, Morris M, Melita AM, Viola R, Forrest Jr JN. cGMP Inhibition of type 3 phosphodiesterase is the major mechanism by which C-type natriuretic peptide activates CFTR in the shark rectal gland. Am J Physiol 306: C343-353, 2014 
7. Ikpa PT, Bijvelds MC, De Jonge HR. Cystic fibrosis: toward personalized therapies. Intl J Biochem Cell Biol 52:192-200, 2014
8. Chen T, Kocinsky HS, Cha B, Murtazina R, Yang J, Tse CM, Singh V, Cole R, Aronson PS, de Jonge H, Sarker R, Donowitz M. Cyclic GMP kinase II (cGKII) inhibits NHE3 by altering its trafficking and phosphorylating NHE3 at three required sites: Identification of a multifunctional phosphorylation site. J Biol Chem 290:1952-1965, 2015
9. Moon C, Zhang W, Ren A, Arora K, Sinha C, Yarlagadda S, Woodrooffe K, Schuetz JD, Valasani KR, de Jonge HR, Shanmukhappa SK, Shata MT, Buddington RK, Parthasarathi K, Naren AP. Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) contributes to drug-induced diarrhea. J Biol Chem 290: 11246-11257, 2015
10. Stahl K, Stahl M, de Jonge HR, Forrest JN Jr. ANP and CNP activate CFTR expressed in Xenopus laevis oocytes by direct activation of PKA. J Recept Signal Transduct Res 27: 1-12, 2015
11. 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
12. Bodewes FA, Bijvelds MJ, de Vries W, Baller JF, Gouw AS, de Jonge HR, Verkade HJ. Cholic acid induces a Cftr dependent biliary secretion and liver growth response in mice. PLoS One. 2015 Feb 13;10:e0117599
13. Vidović D, Carlon MS, F da Cunha M, Dekkers JF, Hollenhorst MI, Bijvelds MJ, Ramalho AS, Van den Haute C, Ferrante M, Baekelandt V, Janssens HM, De Boeck K, Sermet-Gaudelus I, de Jonge HR, Gijsbers R, Beekman JM, Edelman A, Debyser Z. rAAV-CFTRΔR rescues the cystic fibrosis phenotype in human intestinal organoids and CF mice. Am J Respir Crit Care Med 193: 288-98, 2016
14. Yin Y, Bijvelds M, Dang W, Xu L, van der Eijk AA, Knipping K, Tuysuz N, Dekkers JF, Wang Y, de Jonge J, Sprengers D, van der Laan LJ, Beekman JM, Ten Berge D, Metselaar HJ, de Jonge H, Koopmans MP, Peppelenbosch MP, Pan Q. Modeling rotavirus infection and antiviral therapy using primary intestinal organoids. Antiviral Res 123:120-31, 2015
15. Schwarz JS, de Jonge HR, Forrest JN Jr. Value of organoids from comparative epithelia models. Yale J Biol Med 88:367-374, 2015
16. Stahl K, Stahl M, de Jonge HR, Forrest JN Jr. ANP and CNP activate CFTR expressed in Xenopus laevis oocytes by direct activation of PKA. J Recept Signal Transduct Res 35(5):493-504, 2015
17. Yin Y, Wang Y, Dang W, Xu L, Su J, Zhou X, Wang W, Felczak K, van der Laan LJ, Pankiewicz KW, van der Eijk AA, Bijvelds M, Sprengers D, de Jonge HR, Koopmans MP, Metselaar HJ, Peppelenbosch MP, Pan Q. Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development. Antiviral Res 133:41-49. doi: 10.1016/j.antiviral.2016.07.017, 2016
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. Zachos NC, Kovbasnjuk O, Foulke-Abel J, In J, Blutt SE, De Jonge HR, Estes MK, Donowitz M. Human enteroids/colonoids and intestinal organoids functionally recapitulate normal intestinal physiology and pathophysiology. J Biol Chem 291:3759-66, 2016
20. 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
21. Dekkers JF, Berkers G, Kruisselbrink E, Vonk A, de Jonge HR, Janssens HM, Bronsveld I, van de Graaf EA, Nieuwenhuis EE, Houwen RH, Vleggaar FP, Escher JC, de Rijke YB, Majoor CJ, Heijerman HG, de Winter-de Groot KM, Clevers H, van der Ent CK, Beekman JM. Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis. Sci Transl Med 8(344):344ra84, 2016
22. Vijftigschild LA, Berkers G, Dekkers JF, Zomer-van Ommen DD, Matthes E, Kruisselbrink E, Vonk A, Hensen CE, Heida-Michel S, Geerdink M, Janssens HM, van de Graaf EA, Bronsveld I, de Winter-de Groot KM, Majoor CJ, Heijerman HG, de Jonge HR, Hanrahan JW, van der Ent CK, Beekman JM. β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis. Eur Respir J 48(3):768-79, 2016  
23. Van der Mark VA, de Jonge HR, Chang JC, Ho-Mok KS, Duijst S, Vidović D, Carlon MS, Oude Elferink RP, Paulusma CC.The phospholipid flippase ATP8B1 mediates apical localization of the cystic fibrosis transmembrane regulator. Biochim Biophys Acta 1863(9):2280-2288, 2016
24. Ikpa PT, Sleddens HF, Steinbrecher KA, Peppelenbosch MP, de Jonge HR, Smits R, Bijvelds MJ. Guanylin and uroguanylin are produced by mouse intestinal epithelial cells of columnar and secretory lineage. Histochem Cell Biol 146(4):445-55, 2016
25. Debray D, Narkewicz MR, Bodewes FAJA, Colombo C, Housset C, de Jonge HR, Jonker JW, Kelly DA, Ling SC, Poynard T, Sogni P, Trauner M, Witters P, Baumann U, Wilschanski M, Verkade HJ. Cystic fibrosis related liver disease: Research challenges and future perspectives.    
J Pediatr Gastroenterol Nutr 65(4):443-448, 2017 
26. Sheppard DN, Bear CE, de Jonge HR. Editorial overview: Respiratory: Transformational therapies for cystic fibrosis. Curr Opin Pharmacol. 34:viii-xi. doi: 10.1016/j.coph.2017.11.006, 2017 
27. Yin J, Tse CM, Avula LR, Singh V, Foulke-Abel J, de Jonge HR, Donowitz M.Molecular basis and differentiation-associated alterations of anion secretion in human duodenal enteroid monolayers. Cell Mol Gastroenterol Hepatol 5:591-609, 2018
28. 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
29. Romero-Calvo I, Ocon B, Gamez-Belmonte R, Hernandez-Chirlaque C, De Jonge HR, Bijvelds MJ, Martinez-Augustin O, Sanchez de Medina F. Adenylyl cyclase 6 is involved in the hyposecretory states of experimental colitis. Pflugers Arch 470(11):1705-1717, 2018  
30. De Winter-de Groot KM, Janssens HM, van Uum RT, Dekkers JF, Berkers G, Vonk A, Kruisselbrink E, Oppelaar H, Vries R, Clevers H, Houwen RHJ, Escher JC, Elias SG, de Jonge HR, de Rijke JB, Tiddens HAWM, van der Ent CK,  Beekman JM. Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as biomarker of CFTR function. Eur Respir J 17;52(3), 2018
31. Bertolini A, van de Peppel IP, Doktorova-Demmin M, Bodewes FAJA, de Jonge HR, Bijvelds MJC, Verkade HJ, Jonker JW. Defective FXR-FGF15 signaling and bile acid homeostasis in cystic fibrosis mice can be restored by the laxative polyethylene glycol. Am J Physiol Gastrointest Liver Physiol. Am J Physiol Gastrointest Liver Physiol 316(3):G404-G411, 2019 
32. Van de Peppel IP, Doktorova M, Berkers G, de Jonge HR, Houwen RHJ, Verkade HJ, Jonker JW, Bodewes FAJA. Ivacaftor restores FGF19 regulated bile acid homeostasis in cystic fibrosis patients with an S1251N or a G551D gating mutation. J Cyst Fibros 18(2):286-293, 2019
33. van Willigen M, Vonk AM, Yeoh HY, Kruisselbrink E, Kleizen B, van der Ent CK, Egmond MR, de Jonge HR, Braakman I, Beekman JM, van der Sluijs P. Folding-function relationship of the most common cystic fibrosis-causing CFTR conductance mutants. Life Sci Alliance 18;2(1). pii: e201800172. doi: 10.26508/lsa.201800172, 2019
34. Yin YB, de Jonge HR, Wu X, Yin YL. Enteroids for nutritional studies.Mol Nutr Food Res 18:e1801143. doi: 10.1002/mnfr.201801143, 2019
35. Berkers G, van Mourik P, Vonk AM, Kruisselbrink E, Dekkers JF, de Winter-de Groot KM, Arets HGM, Marck-van der Wilt REP, Dijkema JS, Vanderschuren MM, Houwen RHJ, Heijerman HGM, van de Graaf EA, Elias SG, Majoor CJ, Koppelman GH, Roukema J, Bakker M, Janssens HM, van der Meer R, Vries RGJ, Clevers HC, de Jonge HR, Beekman JM, van der Ent CK. Rectal organoids enable personalized treatment of cystic fibrosis. Cell Rep 26(7):1701-1708, 2019
36. 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.

Teaching activities

  • 1976-2010: Lectures and Practical Courses to 200-450 medical students (Basic Biochemistry; Medical Applications; Capita Selecta on Biochemistry and Physiology of the Gastrointestinal Tract); Theme coordinator preclinical teaching programme year 2.
  • (Co)promotor PhD theses 1980-present: 21. 

Other positions

Advisory boards
1983-1988, 1991, 1995-1996 Member Cellular Physiology Study Section, Netherlands Organisation for the Advancement of Pure Research (ZWO/FUNGO-NWO-ZON)
1997-2001 Member Advisory Board Dutch Foundation for Bio-Sciences (NWO-SLW/ALW)
2005 Member RTD-NEST evaluation committee, 6th Framework Programme, EU
2000-2009 Member Advisory Board Flemish Science Organisation (Fonds voor Wetenschappelijk Onderzoek Vlaanderen, FWO, Belgium); section Medical Biochemistry           2000-2003 Consultant Janssen Research Foundation (J&J): Search for new drug   targets in secretory and inflammatory diarrheal states;
2004-2007 Consultant Vertex Pharmaceuticals, San Diego (development CFTR correctors and potentiators)
2006-2009 Consultant Biofocus, Leiden (shRNA screen of CFTR modulator genes)
2006-2015 Moderator ECFS European Young Investigator Meeting (EYIM), Institut Pasteur, Paris
2012-2018 Member Scientific Board ProQR, Leiden (RNA correction therapy of cystic fibrosis).

Scholarships, grants, and awards

1976 Recipient of the Steven Hoogendijk Award (a Dutch Science Prize awarded every two years)
1982-1983 EMBO-Fellowship. Dept. of Chemical Immunology, The Weizmann Institute of Science, Rehovot, Israel (head: Professor S. Shaltiel)
1985 Visiting professor at Columbia University, Dept. of Medicine, Div. of Gastroenterology (head: Professor Michael Field)

Grants (out of 51 since 1978)
2013-2014 PI: Mrace grant ErasmusMC: Use of intestinal organoids in studies of CF and SD; 1 technician; $70.000,-
2014-2016 PI: Grant from ZonMW (=Dutch NIH): CFTR repair by genistein, curcumin and VX-770 (Ivacaftor) in cystic fibrosis patients carrying the S1251N channel gating mutation; 1 postdoc; $420.000,-
2014-2017 PI: Grant from Van der Vorm Foundation, Monaco: CFTR regulation in intestinal organoids; 1 technician; $180.000,-
2013-2015 PI: Grant from PATH/Gates Foundation: testing novel anti-diarrheals in human rectal biopsies and organoids; $90.000,-
2015-2017 PI: Grant Italian Cystic Fibrosis Foundation (FFC): exploitation of a novel CFTR assay in monocytes as a biomarker in clinical trials of CFTR correctors and potentiators; $25.000,-
2015-2017 PI:  Grant Fred Foundation, The Netherlands: assessment and pharmacological correction of abnormalities in  bicarbonate and mucus transport in intestinal biopsies and organoids of cystic fibrosis patients; 1 technician; $80.000,-
2016-2018 PI:  Grant CFF-USA: Bicarbonate transport studies in 2D and 3D intestinal organoids from healthy controls and CF patients; 1 postdoc; $200.000,-
2017-2019 PI: Grant Van der Vorm Foundation, Monaco: Bicarbonate transport defects in CF organoids; 1 technician; $160.000,-
2017-2020 Co-PI: SRC grant UK CF Trust: Restoration of luminal fluidity and microbiota in the CF gut (CFGI-SRC); 1 postdoc; $260.000,-
2019-2021 PI: Grant CFF-USA: Repair of the cystic fibrosis defect in intestinal guanylin signalling;  1 research scientist; $230.000,-
2019-2021 PI: Grant Van der Vorm Foundation, Monaco: Guanylin signalling in epithelial tissues; 1 technician; $160.000,-
2019-2022 co-PI: Grant AlgiPharma, Norway: Use of Oligo-G and nanoparticles to dissolve CF mucus. $240.000,-
2019-2020 co-PI: 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; $60.000,-