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Déterminer les mécanismes moléculaires de la progression de la maladie rénale chronique

de la science fondamentale :
  • signalisation
  • prolifération
  • gènes modificateurs
à la recherche translationnelle :
  • biomarqueurs
  • médecine moléculaire
Fabiola Terzi
Mécanismes et stratégies thérapeutiques des maladies rénales chroniques
Fabiola Terzi, M.D, PhD, is Director of Research of first class at INSERM (Institut National de la Santé et de la Recherche Médicale) and head of the team « Mechanisms and Therapeutic Strategies of Chronic Kidney Disease » at Paris Descartes University, Necker Hospital, France. She obtained a MD from the University of Milan and certified in Pediatrics and Nephrology at the University of Milan. She obtained her PhD in Physiopathology at Paris 7 University. Since 2014, she heads the Department of « Growth & Signaling » at the Institut Necker Enfants Malades, in Paris. She has been awarded the « Grand Prix de l’Académie Nationale de Médecine » and the « Prix de la Fondation du Rein ».

Focus

Chronic kidney disease (CKD) is a major public health concern. Our goal is to dissect the molecular mechanisms leading to CKD progression in order to develop novel therapies and biomarkers susceptible to improve patients care.

Introduction

CKD is characterized by a progressive decline in renal function to end stage renal disease (ESRD) that can occur irrespective of the cause of the renal damage once a critical number of nephrons has been lost. Despite the efforts spent by the health care community, the survival and quality of life of ESRD patients remain poor, in part because of the higher frequency of cardiovascular disease. In addition, CKD often develops on kidney transplants. Accordingly, there is an urgent need to elucidate the mechanisms underlying the progressive destruction of the injured kidney in order to slow down its progression.

Experimental studies have shown that the reduction in the number of functional nephrons triggers molecular and cellular events that promote compensatory growth of the remaining nephrons in order to maintain kidney function. However, over time, the strain imposed by these adaptations results in mechanical and metabolic stress of the remaining nephrons that ultimately leads to pathological changes. This result is a vicious circle in which the loss of nephrons triggers the damage of remnant healthy nephrons. Hence, the rate of CKD progression crucially depends on the ability of remaining nephrons to cope with stress. The identity of the molecular networks at the origin of the initial compensatory renal hypertrophy, and the mechanisms leading to the subsequent appearance of lesions remain to be elucidated.

Research objectives

Our research objectives are at the bases of an extensive research program aimed at unraveling the physiopathology of kidney diseases and take advantage by the peculiar configuration of our team in which scientific investigators and physicians synergistically interact in a continuous exchange of idea and expertise.

Our main scientific goals are:

  • to elucidate the cellular events that result either in renal compensation or deterioration after nephron reduction. We will particularly focus on the role of cell proliferation and differentiation, mechanical, metabolic and genotoxic stresses
  • to dissect the genetic programs and the signaling pathways that trigger these events in podocytes and epithelial tubular cells with a focus on EGFR/STAT3/LCN2, mTORC/AKT2, UPR pathways and modifier genes
  • to extend our experimental finding to the understanding of how these phenomena lead to CKD progression and end-organ damage in Humans in order to identify candidate biomarkers and novel therapeutic strategies susceptible to improve the care of CKD patients.

5 main publications

  • Laouari D, et al (2012) A transcriptional network underlies susceptibility to kidney disease progression. EMBO Mol Med 4:825-839.
  • Canaud G, et al (2013) AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat Med 19:1288-1296.
  • Canaud G, et al (2014) Inhibition of mTORC pathway in the antiphospholipd syndrome. New Engl J Med 371:303-312.
  • El Karoui K, et al (2015) Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2. Nat Commun 7:10330.
  • Bienaimé F, et al (2016) Stat3 controls tubulointerstitial communication during CKD. J Am Soc Nephrol 27:3690-3705.
30 dernières publications

2017

  • Gaillard F, Baron S, Timsit MO, Eladari D, Fournier C, Prot-Bertoye C, Bertocchio JP, Lamhaut L, Friedlander G, Méjean A, Legendre C, Courbebaisse M. What is the significance of ESRD risk estimation in living kidney donors? Transpl Int. 2017 Feb 2. doi: 10.1111/tri.12931. [Epub ahead of print]
  • Avettand-Fenoël V, Rouzioux C, Legendre C, Canaud G. HIV infection in the native and allograft kidney: implications for management, diagnosis, and transplantation. Transplantation. 2017 Feb 11. doi: 10.1097/TP.0000000000001674. [Epub ahead of print]
  • Bienaimé F, Legendre C, Terzi F, Canaud G. Antiphospholipid syndrome and kidney disease. Kidney Int. 2017 Jan;91(1):34-44. Review.
  • 2016

  • Baye E, Gallazzini M, Delville M, Legendre C, Terzi F, Canaud G. The costimulatory receptor B7-1 is not induced in injured podocytes. Kidney Int. 2016 Nov;90(5):1037-1044.
  • Amrouche L, Desbuissons G, Rabant M, Sauvaget V, Nguyen C, Benon A, Barre P, Rabaté C, Lebreton X, Gallazzini M, Legendre C, Terzi F, Anglicheau D. MicroRNA-146a in Human and Experimental Ischemic AKI: CXCL8-Dependent Mechanism of Action. J Am Soc Nephrol. 2016 Jul 21. pii: ASN.2016010045. [Epub ahead of print]
  • Galichon P, Amrouche L, Hertig A, Brocheriou I, Rabant M, Xu-Dubois YC, Ouali N, Dahan K, Morin L, Terzi F, Rondeau E, Anglicheau D. Urinary mRNA for the Diagnosis of Renal Allograft Rejection: The Issue of Normalization. Am J Transplant. 2016 May 27. doi: 10.1111/ajt.13891. [Epub ahead of print]
  • Orhon I, Dupont N, Zaidan M, Boitez V, Burtin M, Schmitt A, Capiod T, Viau A, Beau I, Wolfgang Kuehn E, Friedlander G, Terzi F, Codogno P. Primary-cilium-dependent autophagy controls epithelial cell volume in response to fluid flow. Nat Cell Biol. 2016 Jun;18(6):657-67.
  • Bienaimé F, Muorah M, Yammine L, Burtin M, Nguyen C, Baron W, Garbay S, Viau A, Broueilh M, Blanc T, Peters D, Poli V, Anglicheau D, Friedlander G, Pontoglio M, Gallazzini M, Terzi F. Stat3 Controls Tubulointerstitial Communication during CKD. J Am Soc Nephrol. 2016 May 6. pii: ASN.2015091014. [Epub ahead of print]
  • Bienaimé F, Canaud G, El Karoui K, Gallazzini M, Terzi F. Molecular pathways of chronic kidney disease progression. Nephrol Ther. 2016 Apr;12 Suppl 1:S35-8.
  • Grampa V, Delous M, Zaidan M, Odye G, Thomas S, Elkhartoufi N, Filhol E, Niel O, Silbermann F, Lebreton C, Collardeau-Frachon S, Rouvet I, Alessandri JL, Devisme L, Dieux-Coeslier A, Cordier MP, Capri Y, Khung-Savatovsky S, Sigaudy S, Salomon R, Antignac C, Gubler MC, Benmerah A, Terzi F, Attié-Bitach T, Jeanpierre C, Saunier S. Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation. PLoS Genet. 2016 Mar 11;12(3):e1005894. doi: 10.1371/journal.pgen.1005894. eCollection 2016 Mar.
  • Delville M, Baye E, Durrbach A, Audard V, Kofman T, Braun L, Olagne J, Nguyen C, Deschênes G, Moulin B, Delahousse M, Kesler-Roussey G, Beaudreuil S, Martinez F, Rabant M, Grimbert P, Gallazzini M, Terzi F, Legendre C, Canaud G. B7-1 Blockade Does Not Improve Post-Transplant Nephrotic Syndrome Caused by Recurrent FSGS. J Am Soc Nephrol. 2016 Aug;27(8):2520-7.
  • Rabant M, Amrouche L, Morin L, Bonifay R, Lebreton X, Aouni L, Benon A, Sauvaget V, Le Vaillant L, Aulagnon F, Sberro R, Snanoudj R, Mejean A, Legendre C, Terzi F, Anglicheau D. Early Low Urinary CXCL9 and CXCL10 Might Predict Immunological Quiescence in Clinically and Histologically Stable Kidney Recipients. Am J Transplant. 2016 Jun;16(6):1868-81.
  • Mami I, Tavernier Q, Bouvier N, Aboukamis R, Desbuissons G, Rabant M, Poindessous V, Laurent-Puig P, Beaune P, Tharaux PL, Thervet E, Chevet E, Anglicheau D, Pallet N. A Novel Extrinsic Pathway for the Unfolded Protein Response in the Kidney. J Am Soc Nephrol. 2016 Jan 28. pii: ASN.2015060703. [Epub ahead of print]
  • Zaidan M, Koumakis E, Karras A, Bruneval P, Thervet E, Nochy D. The Case | A man with hypertension, respiratory distress, and rapidly progressive renal failure. Kidney Int. 2016 Feb;89(2):509-10. doi: 10.1016/j.kint.2015.12.014. No abstract available.
  • El Karoui K, Viau A, Dellis O, Bagattin A, Nguyen C, Baron W, Burtin M, Broueilh M, Heidet L, Mollet G, Druilhe A, Antignac C, Knebelmann B, Friedlander G, Bienaimé F, Gallazzini M, Terzi F. Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2. Nat Commun. 2016 Jan 20;7:10330. doi: 10.1038/ncomms10330.
  • Canaud G, Delville M, Legendre C. Recurrence of Focal and Segmental Glomerulosclerosis After Transplantation. Transplantation. 2016 Feb;100(2):284-7.
  • Mami I, Bouvier N, El Karoui K, Gallazzini M, Rabant M, Laurent-Puig P, Li S, Tharaux PL, Beaune P, Thervet E, Chevet E, Hu GF, Pallet N. Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury. J Am Soc Nephrol. 2016 Mar;27(3):863-76. doi: 10.1681/ASN.2015020196. Epub 2015 Jul 20.
  • 2015

  • Canaud G, Legendre C, Terzi F. AKT/mTORC pathway in antiphospholipid-related vasculopathy: a new player in the game. Lupus. 2015 Mar;24(3):227-30.
  • Rabant M, Amrouche L, Lebreton X, Aulagnon F, Benon A, Sauvaget V, Bonifay R, Morin L, Scemla A, Delville M, Martinez F, Timsit MO, Duong Van Huyen JP, Legendre C, Terzi F, Anglicheau D. Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvasive Diagnosis of Antibody-Mediated Kidney Allograft Rejection. J Am Soc Nephrol. 2015 May 6. pii: ASN.2014080797. [Epub ahead of print] PubMed PMID: 25948873.
  • Le Corre S, Viau A, Burtin M, El-Karoui K, Cnops Y, Terryn S, Debaix H, Bérissi S, Gubler MC, Devuyst O, Terzi F. Cystic gene dosage influences kidney lesions after nephron reduction. Nephron. 2015;129(1):42-51.
  • Canaud G. [New insights in the antiphospholipid syndrome associated vasculitis: The role of the AKT/mTORC pathway]. Rev Med Interne. 2015 Mar 10. pii: S0248-8663(15)00073-9. doi: 10.1016/j.revmed.2015.02.006. [Epub ahead of print] French. PubMed PMID: 25769629.
  • Delville M, Baye E, Durrbach A, Audard V, Kofman T, Braun L, Olagne J, Nguyen C, Deschênes G, Moulin B, Delahousse M, Kesler-Roussey G, Beaudreuil S, Martinez F, Rabant M, Grimbert P, Gallazzini M, Terzi F, Legendre C, Canaud G. B7-1 Blockade Does Not Improve Post-Transplant Nephrotic Syndrome Caused by Recurrent FSGS. J Am Soc Nephrol. 2015 Dec 23. pii: ASN.2015091002. [Epub ahead of print]
  • Rabant M, Amrouche L, Morin L, Bonifay R, Lebreton X, Aouni L, Benon A, Sauvaget V, Le Vaillant L, Aulagnon F, Sberro R, Snanoudj R, Mejean A, Legendre C, Terzi F, Anglicheau D. Early low urinary CXCL9 and CXCL10 might predict immunological quiescence in clinically and histologically stable kidney recipients. Am J Transplant. 2015 Dec 23. doi: 10.1111/ajt.13677. [Epub ahead of print]
  • Canaud G, Loupy A. Focal Segmental Glomerulosclerosis Recurrence: Soluble Urokinase Receptor Left Out? Transplantation. 2015 Dec;99(12):2449-50.
  • Chemouny JM, Suberbielle C, Rabant M, Zuber J, Alyanakian MA, Lebreton X, Carmagnat M, Pinheiro N, Loupy A, Van Huyen JP, Timsit MO, Charron D, Legendre C, Anglicheau D. De Novo Donor-Specific Human Leukocyte Antigen Antibodies in Nonsensitized Kidney Transplant Recipients After T Cell Mediated Rejection. Transplantation. 2015 May;99(5):965-72.
  • 2014

  • Liang N, Zhang C, Dill P, Panasyuk G, Pion D, Koka V, Gallazzini M, Olson EN, Lam H, Henske EP, Dong Z, Apte U, Pallet N, Johnson RL, Terzi F, Kwiatkowski DJ, Scoazec JY, Martignoni G, Pende M. Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex. J Exp Med. 2014 Oct 20;211(11):2249-63.
  • Canaud G, Bienaimé F, Tabarin F, Bataillon G, Seilhean D, Noël LH, Dragon-Durey MA, Snanoudj R, Friedlander G, Halbwachs-Mecarelli L, Legendre C, Terzi F. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med. 2014 Jul 24;371(4):303-12.
  • Gleixner EM, Canaud G, Hermle T, Guida MC, Kretz O, Helmstädter M, Huber TB, Eimer S, Terzi F, Simons M. V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis. Cell Rep. 2014 Jul 10;8(1):10-9.
  • Canaud G, Dejucq-Rainsford N, Avettand-Fenoël V, Viard JP, Anglicheau D, Bienaimé F, Muorah M, Galmiche L, Gribouval O, Noël LH, Satie AP, Martinez F, Sberro-Soussan R, Scemla A, Gubler MC, Friedlander G, Antignac C, Timsit MO, Onetti Muda A, Terzi F, Rouzioux C, Legendre C. The kidney as a reservoir for HIV-1 after renal transplantation. J Am Soc Nephrol. 2014 Feb;25(2):407-19.
  • Zaidan M, Palsson R, Merieau E, Cornec-Le Gall E, Garstka A, Maggiore U, Deteix P, Battista M, Gagné ER, Ceballos-Picot I, Duong Van Huyen JP, Legendre C, Daudon M, Edvardsson VO, Knebelmann B. Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure. Am J Transplant. 2014 Nov;14(11):2623-32.
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    Parrain(s)
    S.A.R. la Princesse Caroline de Hanovre qui, à travers la Fondation Princesse Grace, soutient déjà la recherche medicale et tout ce qui contribue à soulager les enfants malades en France et dans le monde, a accepté de s'engager à nos cotés pour que ce centre de medecine moleculaire, tourné entre autres vers les pathologies des enfants, prenne de vitesse les maladies et continue à relever les defis actuels.

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