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.
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 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.
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.
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.
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.
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.
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Arndt G Benecke, Ph.D.
CNRS UMR8246, UPMC UM119, INSERM UMRS1130
Institut de Biologie Paris Seine
Universite Pierre & Marie Curie
7, Quai Saint Bernard
+33 (0)1 44 27 91 35
arndt.benecke [at] upmc.fr
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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
+34 (0) 932 607 137
apujol [at] idibell.cat