HCR.20.073 – From latent metabolic dysregulation in neurodevelopmental disorders to stress tolerance and resilience in health and disease – BALANCE

Route: Health care research, sickness prevention and treatment

Cluster question: 077 What do non-genetic factors contribute to personal traits and disease processes?

Mendelian NeuroDevelopmental Disorders (NDDs) represent a major unsolved medical and socio-economic problem. The only so far treatable NDDs are inborn errors of metabolism. They can be alleviated by strategies such as nutraceutical supplementation or substrate reduction, enzyme replacement therapy, or stimulation of alternate pathways.
Based on our recent research, we will explore a novel, underappreciated, but potentially very common class of latent metabolic NDDs that could be targeted equally. The contribution of metabolic aberrations in these disorders has gone largely unnoticed because their causative genes operate in non-metabolic cellular processes. Moreover, significant environmental insults (stressors) such as oxidative stress, infection, DNA damage, sleep deprivation, or aging are required for patients to get ‘out of balance’ and start presenting with defects in energy/redox metabolism and associated symptoms.
The BALANCE consortium aims to begin uncovering and understanding latent metabolic NDDs and identify novel treatment targets. Our objectives are to: (i) obtain comprehensive mechanistic insights into the potentially widely exploitable findings that optimal energy/redox metabolism confers tolerance and resilience to disease-accelerating stressors; (ii) identify NDDs that suffer from latent metabolic dysregulation using Drosophila and induced Pluripotent Stem Cells, supported by nanosensor chip technology, as timely and highly efficient model systems; (iii) identify novel treatment strategies for latent metabolic NDDs and work towards their implementation, and (iv) exploit the gained insights in the energetic/redox basis of stress tolerance/resilience to develop nutritional and immunotherapeutic strategies to sustain health in the diseased and general population.
In close collaboration with various partners and stakeholders, this multidisciplinary consortium of leading experts in neurodevelopmental and metabolic disorders, immunology and physiology will provide fundamental insights into the metabolic mechanisms of diseases and stress responses, develop treatment strategies for NDDs, and leverage the potential of the gained knowledge to improve stress tolerance, resilience, and healthy living in the general population.
Fundamental partners: 1. Radboudumc (RUMC): A. Schenck (Prof. Translational Genomics of Neurodevelopmental Disorders); N. Nadif Kasri (Assoc. Prof. Molecular Neurophysiology); T. Kleefstra (Prof. Clinical Genetics and Psychopathology of Rare Syndromes); M. Netea (Prof. Experimental Internal Medicine); R. P. van Rij (Prof. Experimental Virology); C. van Karnebeek (Prof. Metabolic Diseases); W. Koopman (Assoc. Prof. Cellular Bioenergetics). 2. Amsterdam UMC: R. Houtkooper (Prof. Translational Metabolism). 3. Erasmus MC (EMC) & Princess Maxima Center for Pediatric Oncology: J.H.J. Hoeijmakers (Prof. Molecular Genetics). 4. UT: S. Le Gac (Prof. Applied Microfluidics for Bioengineering Research). 5. WUR: J. Keijer (Prof. Human and Animal Physiology). 6. (Money Follows Cooperation) University of South Bohemia, CZ: T. Dolezal (Assoc. Prof. Molecular Integrative Physiology). Other institutions/organisations: Inholland University of Applied Sciences Delft-Amsterdam. Food and Biobased Research (Wageningen Research, T2O). Expertise center for epilepsy, sleep medicine, learning and development disabilities Kempenhaeghe. Euretos (AI platform). Multi Channel Systems (nanotechnology). Patient organisations for neurodevelopmental syndromes.

Keywords

alternative in vivo models, brain on a chip, Drosophila, drug testing, immune challenge, intervention, iPSCs, mendelian genetic syndromes, metabolic sensors, metabolism, minimizing use of animal models, nanosensing, nanotechnology, neurodevelopmental disorders, nutrition, resilience, sleep, Stress, stress tolerance

Other organisations

Amsterdam UMC, CZ, Erasmus Medical Center (EMC), Euretos (AI platform), Expertise center for epilepsy, Inholland University of Applied Sciences Delft-Amsterdam, learning and development disabilities Kempenhaeghe, Multi Channel Systems (nanotechnology), Patient organisations for neurodevelopmental syndromes., Princess Maxima Center for Pediatric Oncology, Radboud Medical Center (RUMC), sleep medicine, University of South Bohemia, UT, Wageningen Universities and Research (WUR), WUR

Submitter

Organisation Radboud University Medical Center (RUMC)
Name Dr. A. (Annette) Schenck
E-mail Annette.Schenck@radboudumc.nl
Website https://www.radboudumc.nl/translational-genomics-of-neurodevelopmental-disorders