Aurora Pujol

Dr. Pujol is a world-renowned expert for demyelinating disease and medical systems genetics. Her work has directly lead to the central hypothesis of this ambitious project being that cellular metabolism is the key to understanding demyelinating disease and its onset through immune activation.

Arndt G Benecke

Dr. Benecke is internationally recognized for his innovative use of systems biology in innate immunity. He has directly contributed to the development of the state-of-the-art comp. approaches for dimensionality reduction, pattern matching, and genome-metabolic simulations.

Daniel Raya

Daniel is CEO and co-founder of Advanced Systems Genetics SL. His original background is in telecomunications and business development. AdSysGen offers its services as a consulting company and provides innovative, integrated solutions for systems genetics pre-clinical, clinical and basic research to non-profit and for-profit organizations.

NEUROM. Computational Modeling of Human Brain Metabolism and Immune Activation triggering the Onset of Rare and Common Demyelinating Disease.

Multiple sclerosis (M.S.) and X-linked adrenoleukodystrophy (X-ALD) are complex neurodegenerative diseases, thought to arise through a combination of deregulated lipid metabolism and homeostasis due to genetic variations and by immune activation. In MS, environmental risk factors linked to the disease in one population tend to be unimportant in other populations. For both, the homeostasis of lipid metabolism may collapse during acute- phase inflammatory response triggered by a pathogen, trauma, or stress, starting a feedback loop of increased oxidative stress, inflammatory response, and proliferation of cytoxic foam cells that cross the blood brain barrier and both catabolize myelin and prevent remyelination.

Understanding X-ALD and M.S. as chronic metabolic disorders suggests new avenues for treatment.

Here, we leverage this paradigm in the context of X-ALD and M.S. to specifically address the interconnections of innate immune sensing and activation with human metabolism and intersect those with the pathways and regulatory events associated with demyelinating disease in X-ALD and M.S.

Overall Strategy.

Functional genomics data from different disease and infection models feed our computational approach consisting in the inference of the master regulators of the gene regulatory response networks. Using FBA/MCA deconvoluted and integrated ‘omics’ profiles are directly scrutinized for metabolic activity and lipid homeostasis. Our strategy will define: (i) integrated biomarkers and signatures for X-ALD and M.S., (ii) novel therapeutic targets for control of aberrant metabolism, and (iii) define the common and distinct mechanisms of disease onset and progression.

Computational Approach.

Integration of different systems biology approaches. Functional genomics data from different infections and disease models feed our computational approach consisting in the inference of the master regulators of the gene regulatory response networks. In an highly complementary computational approach involving FBA/MCA simulations targets are matched A machine learning iterative cycle of the projects overall approach generates more refined predictions and synergy and is the essential basis for stratifying bench to bedside.

Metabolic Modeling.

Our unique computational methodology will classify host responses and infer mechanisms of innate immune activation in silico against relevant X-ALD and M.S. disease onset and progression markers identified in Aim 2 in an effort to understand and characterize the deep link between demyelinating disease onset and immune activation in response to benign or pathogenic infections. The combination of Flux-Balance Analysis (FBA) / Metabolic Control Analysis (MCA) with machine learning methodology will ensure improved performance and reliability over time with increasing amounts of available data through the project’s synergistic, iterative interactions.

Selected Publications.

  1. Morató L, Galino J, Ruiz M, Calingasan NY, Starkov AA, Dumont M, Naudí A, Martínez JJ, Aubourg P, Portero-Otín M, Pamplona R, Galea E, Beal MF, Ferrer I, Fourcade S, Pujol A. Pioglitazone halts axonal degeneration in a mouse model of X-linked adrenoleukodystrophy. Brain. 2013 Jun 22.

  2. Ghosh T, Aprea J, Nardelli J, Engel H, Selinger C, Mombereau C, Lemonnier T, Moutkine I, Schwendimann L, Dori M, Irinopoulou T, Henrion-Caude A, Benecke AG, Arnold SJ, Gressens P, Calegari F, Groszer M. MicroRNAs establish robustness and adaptability of a critical gene network to regulate progenitor fate decisions during cortical neurogenesis. Cell Rep. 2014 Jun 26;7(6):1779-88.

  3. López-Erauskin J, Galino J, Bianchi P, Fourcade S, Andreu AL, Ferrer I, Muñoz-Pinedo C, Pujol A. Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy. Brain. 2012 Dec;135(Pt 12):3584-98.

  4. Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP, Brining D, Bushmaker T, Martellaro C, Baseler L, Benecke AG, Katze MG, Munster VJ, Feldmann H. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med. 2013 Oct;19(10):1313-7.

  5. Galea E, Launay N, Portero-Otin M, Ruiz M, Pamplona R, Aubourg P, Ferrer I, Pujol A. Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: A paradigm for multifactorial neurodegenerative diseases? Biochim Biophys Acta. 2012 Sep;1822(9):1475-88.

  6. Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, Walther A, Tauber P, Schwarzmayr T, Diener S, Graf E, Allolio B, Samson-Couterie B, Benecke AG, Quinkler M, Fallo F, Plouin PF, Mantero F, Meitinger T, Mulatero P, Jeunemaitre X, Warth R, Vilsen B, Zennaro MC, Strom TM, Reincke M. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013 Apr;45(4):440-4, 444e1-2.

  7. S Fourcade, J López-Erauskin, J Galino, C Duval, A Naudi, M Jove, S Kemp, F Villarroya, I Ferrer, R Pamplona, M Portero-Otin, A Pujol (2008). Early oxidative damage underlying neurodegeneration in Xadrenoleukodystrophy. Human Molecular Genetics. Jun 15;17(12):1762-73.

  8. Benecke AG. Chromatin code, local non-equilibrium dynamics, and the emergence of transcription regulatory programs. Eur Phys J E Soft Matter. 2006 Mar;19(3):353-66.

  9. Morató L, Ruiz M, Boada J, Calingasan NY, Galino J, Guilera C, Jové M, Naudí A, Ferrer I, Pamplona R, Serrano M, Portero-Otín M, Beal MF, Fourcade S, Pujol A. Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy. Cell Death Differ. 2015 Mar 27. doi: 10.1038/cdd.2015.20. [Epub ahead of print].

  10. Jacquelin B, Mayau V, Targat B, Liovat AS, Kunkel D, Petitjean G, Dillies MA, Roques P, Butor C, Silvestri G, Giavedoni LD, Lebon P, Barré-Sinoussi F, Benecke AG, Müller-Trutwin MC. Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest. 2009 Dec;119(12):3544-55.

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Arndt G Benecke, Ph.D.


Institut de Biologie Paris Seine
Universite Pierre & Marie Curie

7, Quai Saint Bernard
75005 Paris

+33 (0)1 44 27 91 35

arndt.benecke [at]

48.847699, 2.359245

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Aurora Pujol, M.D. Ph.D.

Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)

Hospital Duran i Reynals

Gran Via 199
08907, L'Hospitalet del Llobregat
Barcelona, Spain

+34 (0) 932 607 137

apujol [at]

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