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TIM VANMIERLO - REPAIR-INDUCING COGNITION ENHANCERS (RICE)

"SCIENCE FOR PATIENTS"


Therapeutic research in neurodegeneration mainly focusses on molecular mechanisms and disease hallmarks, but improvement on the functional level is often neglected. Therefore, the “repair team” of the NIC&R group couples a cognitive readout to molecular interventions in treatment of CNS damage so that we can provide a translational interpretation towards first-in-man trials. We focus on neurodegenerative disorders such as multiple sclerosis and Alzheimer’s disease.

 

You can contact us for:

  1. Functional and molecular readouts in animal models of multiple sclerosis and Alzheimer’s disease
  2. Molecular and cellular setups in relation to oligodendrocyte differentiation
  3. In vitro and in vivo gene-editing tools to modulate (epi)genetic processes on the cellular level (e.g. CRISPR/Cas9, in vivo micro-electroporation)

 

Short Bio

Peer reviewed pubmed (ncbi) publications: 58

Hirsch index Web of Science: H=20 (Sum of citations: 1097)

Hirsch index Google scholar : H=22 (Sum of citations: 1549)

  

  1. Tiane A., Schepers M., Rombaut B., Hupperts R., Prickaerts J., Hellings N., van den Hove D., Vanmierlo T.From OPC to oligodendrocyte – an epigenetic journey Cells. 2019 Oct 11;8(10). pii: E1236. (IF 5.66)
  2. Schepers M., Tiane A., Paes D., Sanchez S., Rombaut B., Piccart E., Rutten B.P.F., Brône B., Hellings N., Prickaerts J., Vanmierlo T. Targeting phosphodiesterases – towards a tailor-made approach in multiple sclerosis treatment Front. Immunol., 24 July 2019 Front Immunol. 2019 Jul 24; 10:1727 (IF 4.72)
  3. Bogie J.*, Hoeks C.*, Schepers M, Tiane A., Cuypers A., Leijten F., Chintapakorn Y, Suttiyut T, Pornpakakul S., Struik D., Kerksiek A., Liu H.B., Hellings N., Martinez-Martinez P., Jonker J.W., Dewachter I., Sijbrands E., Walter J., Hendriks J., Groen A.K., Staels B., Lütjohann D., Mulder M.* & Vanmierlo T.* Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer's disease mouse model. Sci Rep. 2019 Mar 20;9(1):4908. (IF 4.01)
  4. Plat J, Baumgartner S, Vanmierlo T, Lütjohann D, Calkins KL, Burrin DG, Guthrie G, Thijs C, Te Velde AA, Vreugdenhil ACE, Sverdlov R, Garssen J, Wouters K, Trautwein EA, Wolfs TG, van Gorp C, Mulder MT, Riksen NP, Groen AK, Mensink R Consequences of human development in a plant-based environment. Prog Lipid Res. 2019 Apr;74:87-102. (IF 12.54)
  5. Blokland A., Heckman P., Vanmierlo T., Schreiber R., Paes D., Prickaerts J. Phosphodiesterase type 4 inhibition in CNS diseases Trends in pharmacological sciences 2019 in press (IF 11.52)

IP

10/10/2019 publication PCT Patent with Application numbers EP18165843.6  PCT/EP2019/05495 WO 2019/193091 on “Selective PDE4D inhibitors against demyelinating diseases”

 

Elisabeth (Lize) Piccart (postdoc)

Multiple sclerosis is a devastating disease that affects over one million people worldwide and many effective therapeutics are available. However, up to 65% of patients transgress to progressive MS, for which no therapeutics are available to date. Therefore, I will join hands with Rewind Therapeutics within the framework of a VLAIO innovation mandate, so that we can develop a promising, novel target in the treatment of progressive MS and help bridge the gap between academia and industry. 

Selected publications

  1. Piccart E., Courtney N.A., Ford C.P., Beckstead M.J. Neurotensin induces long-term depression of D2 dopamine autoreceptor-mediated neurotransmission in midbrain dopaminergic neurons. Journal of neuroscience (2015). IF:7.271.
  2. Dominguez-Lopez S., Piccart E., Lynch W.B., Wollet M.B., Sharpe A.L., Beckstead M.J.  Antagonism of Neurotensin Receptors in the Ventral Tegmental Area Decreases Methamphetamine Self-Administration and Methamphetamine Seeking in Mice. Int J Neuropsychopharmacol. (2018) 1;21(4):361-370. IF: 4.009
  3. Molchanova SM, Comhair J, Karadurmus D, Piccart E, Harvey RJ, Rigo JM, Schiffmann SN, Brône B, Gall D.  Tonically Active α2 Subunit-Containing Glycine Receptors Regulate the Excitability of Striatal Medium Spiny Neurons. Front Mol Neurosci. (2018) 9;10:442. IF: 5.076
  4. Piccart E., Tschumi C., Beckstead M.J. PCP attenuates D2 autoreceptor signaling in SNc dopamine neurons. Resubmitted to European Neuropsychopharmacology. IF: 4.369 
  5. Schepers, Melissa; Tiane, Assia; Paes, Dean; Sanchez, Selien; Rombaut, Ben; Piccart, E; Rutten, Bart P. F.; Brone, Bert; Hellings, Niels; Prickaerts, Jos; Vanmierlo, Tim. Targeting Phosphodiesterases-Towards a Tailor-Made Approach in Multiple Sclerosis Treatment. Frontiers in Immunology, Vol. 10, 1727, 24.07.2019, p. 1-17. IF: 4.716

Tools: in vivo patch clamp electrophysiology, behavioral analysis of mouse models

 

 

Melissa Schepers (PhD student)

The neuro-degenerative disorder Multiple Sclerosis is in its progressive form featured by persistent demyelination of the central nervous system and is characterized by devastating symptoms including muscle weakness, fatigue and cognitive impairements, but therapeutic interventions are currently still lacking. Therefore, in this project, we are aiming to inhibit a specific class of enzymes called “phosphodiesterases” by means of CRISPR/Cas9 at a cellular level so that the endogenous repair mechanism called “remyelination” can be enhanced to stimulate repair in progressive MS patients.

You can contact us for:

  • Cognitive testing
  • Oligodendrocyte differentiation assessment
  • Genetic editing by means of CRISPR/Cas9

Short Bio 

Publications

  1. Schepers M., Martens N., Tiane A., Vanbrabant K., Liu H.B., Lütjohann D., Mulder M*. & Vanmierlo T.*
    Edible seaweed-derived constituents, an undisclosed source of neuroprotective compounds
    Neural Regen Res. 7 Aug 2019 In press (IF 2.47)
  2. Schepers M., Tiane A., Paes D., Sanchez S., Rombaut B., Piccart E., Rutten B.P.F., Brône B., Hellings N., Prickaerts J., Vanmierlo T. Targeting phosphodiesterases – towards a tailor-made approach in multiple sclerosis treatment Front. Immunol., 24 July 2019 Front Immunol. 2019 Jul 24; 10:1727 (IF 4.72)
  3. Tiane A., Schepers M., Rombaut B., Hupperts R., Prickaerts J., Hellings N., van den Hove D., Vanmierlo T.From OPC to oligodendrocyte – an epigenetic journey Cells. 2019 Oct 11;8(10). pii: E1236. (IF 5.66)
  4. Bogie J.*, Hoeks C.*, Schepers M, Tiane A., Cuypers A., Leijten F., Chintapakorn Y, Suttiyut T, Pornpakakul S., Struik D., Kerksiek A., Liu H.B., Hellings N., Martinez-Martinez P., Jonker J.W., Dewachter I., Sijbrands E., Walter J., Hendriks J., Groen A.K., Staels B., Lütjohann D., Mulder M.* & Vanmierlo T.* Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer's disease mouse model. Sci Rep. 2019 Mar 20;9(1):4908. (IF 4.01)
  5. Amanda Santiago, Lígia Mendes Soares, Melissa Schepers, Humberto Milani, Tim Vanmierlo, Jos Prickaerts, Rúbia M Weffort de Oliveira; Rofliumilast promotes memory recovery and attenuates white matter injury in aged rats subjected to chronic cerebral hypoperfusion. Neuropharmacology; 2018; IF 4.25

 Video

https://youtu.be/1-ZP4A9eBMY

https://youtu.be/bJ9yv3iGEy0

 

 

  

Dean Paes (PhD student)

 

PDE4 inhibitors shows potential to restore impaired memory consolidation in both animals and humans, but this pharmacological intervention gives rise to adverse side effects. Therefore, I study the role of specific PDE4 isoforms in memory processes and Alzheimer’s disease so that more specific and safer interventions can be developed.

Short Bio https://www.linkedin.com/in/deanpaes/  
https://www.sciencefiguredout.be/alzheimers-disease-forget-about-it

 

You can contact us for:

  • In silico target identification and specification: Exon composition mapping, isoform expression profiling (qPCR and NGS/Exon Array data), and high-throughput molecular modelling/docking.
  • In vitro target validation: Isoform-specific knockout, and neuronal differentiation/plasticity assessment.
  • In vivo target validation:  Pharmacological intervention and cognitive phenotyping in rodents.

 

Publications

  1. Paes D, Lardenoije R, Carollo RM, Roubroeks JAY, Schepers M, Coleman P, Mastroeni D, Delvaux E, Pishva E, Lunnon K, Vanmierlo T, van den Hove D, Prickaerts J. Increased isoform-specific phosphodiesterase 4D expression is associated with pathology and cognitive impairment in Alzheimer's disease. Neurobiol Aging. 2021 Jan;97:56-64. doi: 10.1016/j.neurobiolaging.2020.10.004.
  2. Paes D, Xie K, Wheeler DG, Zook D, Prickaerts J, Peters M. Inhibition of PDE2 and PDE4 synergistically improves memory consolidation processes. Neuropharmacology. 2020 Nov 26;184:108414. doi: 10.1016/j.neuropharm.2020.108414.
  3. McQuown S, Paes D, Baumgärtel K, Prickaerts J, Peters M. Pharmacological inhibition of phosphodiesterase 7 enhances consolidation processes of spatial memory. Neurobiol Learn Mem. 2020 Dec 3;177:107357. doi: 10.1016/j.nlm.2020.107357.
  4. Blokland A, Heckman P, Vanmierlo T, Schreiber R, Paes D, Prickaerts J. Phosphodiesterase Type 4 Inhibition in CNS Diseases. Trends Pharmacol Sci. 2019 Dec;40(12):971-985. doi: 10.1016/j.tips.2019.10.006.
  5. Schepers M, Tiane A, Paes D, Sanchez S, Rombaut B, Piccart E, Rutten BPF, Brône B, Hellings N, Prickaerts J, Vanmierlo T. Targeting Phosphodiesterases-Towards a Tailor-Made Approach in Multiple Sclerosis Treatment. Front Immunol. 2019 Jul 24;10:1727. doi: 10.3389/fimmu.2019.01727.

 

 

Assia Tiane (PhD student)

During the progressive stages of MS, endogenous remyelination is hampered due to the inability of OPCs to differentiate into myelin-producing cells. Increasing evidence shows that epigenetics, and in particular DNA-methylation, plays a crucial role in OPC differentiation, but the underlying mechanism remains unclear. Therefore, we investigate the epigenome-wide methylation profile of progressive MS patients, so that it can be used as a blood-borne biomarker for remyelination, as well as provide new therapeutic targets for progressive MS.

You can contact us for:

  • Oligodendrocyte differentiation
  • Epigenetic editing (CRISPR-dCas)
  • Pyrosequencing

 

Short bio available on:  https://www.linkedin.com/in/assia-tiane/

 

Publications:

  1. Tiane A., Schepers M., Rombaut B., Hupperts R., Prickaerts J., Hellings N., van den Hove D., Vanmierlo T.From OPC to oligodendrocyte – an epigenetic journey Cells. 2019 Oct 11;8(10). pii: E1236. (IF 5.66)
  2. Schepers M., Martens N., Tiane A., Vanbrabant K., Liu H.B., Lütjohann D., Mulder M*. & Vanmierlo T.* Edible seaweed-derived constituents, an undisclosed source of neuroprotective compounds Neural Regen Res. 7 Aug 2019 In press (IF 2.47)
  3. Schepers M., Tiane A., Paes D., Sanchez S., Rombaut B., Piccart E., Rutten B.P.F., Brône B., Hellings N., Prickaerts J., Vanmierlo T. Targeting phosphodiesterases – towards a tailor-made approach in multiple sclerosis treatment Front. Immunol., 24 July 2019 Front Immunol. 2019 Jul 24; 10:1727 (IF 4.72)
  4. Bogie J.*, Hoeks C.*, Schepers M, Tiane A., Cuypers A., Leijten F., Chintapakorn Y, Suttiyut T, Pornpakakul S., Struik D., Kerksiek A., Liu H.B., Hellings N., Martinez-Martinez P., Jonker J.W., Dewachter I., Sijbrands E., Walter J., Hendriks J., Groen A.K., Staels B. , Lütjohann D., Mulder M.* & Vanmierlo T.* Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer's disease mouse model. Sci Rep. 2019 Mar 20;9(1):4908. (IF 4.12)

 https://youtu.be/T45kzlA_cF8

 

 

Ben Rombaut (PhD student)

Alzheimer’s disease is characterized as a neurodegenerative disease, mainly recognizable by its hallmarks (Aβ plaques and Tau tangles) and synaptic dysfunction, but main therapeutic strategies targeting the major hallmarks remain ineffective. Therefore, we aim to investigate the role of microglia in the excessive synaptic elimination witnessed in early stages of AD so that an effective treatment strategy can be found regarding synaptopathologies.

You can contact us for:

  • Functional and molecular readouts in animal models of multiple sclerosis and Alzheimer’s disease
  • Molecular and cellular setups in relation to microglial functioning
  • In vitro and in vivo gene-editing tools to modulate (epi)genetic processes on the cellular level

(e.g. CRISPR/Cas9, in vivo micro-electroporation)

Short bio 


Publications:

  1. Tiane A., Schepers M., Rombaut B., Hupperts R., Prickaerts J., Hellings N., van den Hove D., Vanmierlo T.From OPC to oligodendrocyte – an epigenetic journey Cells. 2019 Oct 11;8(10). pii: E1236. (IF 5.66)
  2. Schepers M., Tiane A., Paes D., Sanchez S., Rombaut B., Piccart E., Rutten B.P.F., Brône B., Hellings N., Prickaerts J., Vanmierlo T. Targeting phosphodiesterases – towards a tailor-made approach in multiple sclerosis treatment Front. Immunol., 24 July 2019 Front Immunol. 2019 Jul 24; 10:1727 (IF 4.72)

 

Philippos Koulousakis (PhD student)

Alzheimer’s Disease (AD) is a fatal progressive neurodegenerative disease. Only about 10% of cases can be explained solely due to genetic predispositions. Epigenetic differences, altering gene expression without changing the DNA sequence play a significant role. We aim to epigenetically alter different genes that have been established as candidate genes from Epigenome Wide Association Studies (EWAS) in vitro and in vivo. We hope to establish a pipeline of testing methods to investigate a reliable cause-and-effect for candidate genes. One of these is the neuropeptide Oxytocin (OXT), which has been studied in different context, but not in AD. The project is in collaboration with Prof. van den Hove (Maastricht University).

You can contact us for:

  • Epigenetic Editing
  • Pyrosequencing
  • Behavioral testing
  1. Koulousakis P, van den Hove D, Riemens R, Pishva, E. Epigenome-wide association studies in Alzheimer’s Disease; Achievements and Challenges. Brain Pathology. 2019 (In Press).
  2. Koulousakis P, van den Hove D, Visser-Vandewalle V, Sesia T. Cognitive Improvements after Intermittent Deep Brain Stimulation of the Nucleus Basalis of Meynert in a Transgenic Rat Model for Alzheimer’s disease; a Preliminary Approach. Journal of Alzheimer’s Disease. 2019 (In Press).
  3. Koulousakis P, Andrade P, Visser-Vandewalle V, Sesia T. The Nucleus Basalis of Meynert and Its Role in Deep Brain Stimulation for Cognitive Disorders: A Historical Perspective. Journal of Alzheimer's Disease. 2019 Jan 1(Preprint):1-5.

 

 

Lieve van Veggel (PhD student)

The lack of remyelination due to the inability of OPCs is thought to play a significant role in the progression of Multiple Sclerosis (MS). Therapeutic interventions preventing or delaying disease progression are currently not available. In my project, I focus on modulating the excitatory amino acid transporter 3 (EAAT3) to protect OPCs against oxidative stress and thus allow differentiation. In addition, I will employ structure-based drug discovery strategies to design a lead compound and potentially develop a novel treatment strategy targeting the progression of MS. 
 
You can contact us for:
  • Oligodendrocyte differentiation
  • Basic modeling and docking studies
  • Biochemical design
 
Short bio available here: https://www.linkedin.com/in/lvveggel/
 
Publications:
1. Roggeri, A.; Schepers, M.; Tiane, A.; Rombaut, B.; van Veggel, L.; Hellings, N.; Prickaerts, J.; Pittaluga, A.; Vanmierlo, T. Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation. Int. J. Mol. Sci. 2020, 21, 7537. (IF 4.556)
 
  • Oligodendrocyte differentiation
  • Epigenetic editing (CRISPR-dCas)
  • Pyrosequencing
  • Functional and molecular readouts in animal models of multiple sclerosis and Alzheimer’s disease
  • Molecular and cellular setups in relation to microglial functioning
  • In vitro and in vivo gene-editing tools to modulate (epi)genetic processes on the cellular level
  • (e.g. CRISPR/Cas9, in vivo micro-electroporation)
  • In silico: Exon composition mapping and isoform expression profiling (using ExonArray data or qPCR).
  • In vitro:Isoform-specific knockdown and characterization of neuronal differentiation.
  • In vivo: Cognitive phenotyping of rodents in behavioural tests.