The Fitzsimons Lab

After a postdoctoral experience at the Leiden-Amsterdam Center for Drug Research, aimed to study the behavioral consequences for cognition of gene knockdown using RNA interference, I joined the Center for Neurosciences, SILS, UvA as Assistant professor in 2010, within  the group Structural and Functional Plasticity of the Nervous System lead by Prof. Paul Lucassen.
My lab is financed by a VIDI subsidy from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO).

My lab studies the regulation of neural stem cells by hormones and microRNAs. In particular, alterations in adult neurogenesis associated with acute and chronic stress, epilepsy, neurodegenerative diseases and depression.

 

News

The International Foundation for Alzheimer's Research (Internationale Stichting Alzheimer Onderzoek (ISAO)) has recently funded 10 new research lines to a total of 1.100.000 euro. I feel very proud that my lab is one of the awardees. The project is aimed to investigate the epigenetic programming of hippocampal neurogenesis by stress in sporadic Alzheimer’s disease models.

Most current animal models of Alzheimer’s disease (AD) are based on the expression of mutated genes associated with the familiar form of AD. These models have played a major role in identifying pathological mechanisms linked to and in evaluating novel therapies. However, familial AD affects only a minority of AD patients. Moreover, in these models pathology starts early in life and is driven fundamentally by the expression of the mutated gene, making them especially unsuitable for the study of the effect of environmental factors, such as stress, on AD progression.

More information can be found at:

https://www.alzheimer.nl/onderzoek/onderzoeksprojecten/2014

This project covers experimentally a part of the concepts on epigenetic regulation of neural stem cells we have put forward in a recent article published in a highly accessed article in Molecular Neurodegeneration, a Journal dedicated to all aspects of neurodegeneration research at the molecular and cellular levels. This article is open access and can be found at:

http://www.molecularneurodegeneration.com/content/9/1/25 

 

This year (2014), Erik Betzig, Stefan W. Hell and W. E. Moerner received the the Nobel Prize in Chemistry 2014 for the development of super-resolution fluorescence microscopy. This is a group of techniques developed to overcome the long-standing limitation imposed by light's diffraction limit. Before this development diffraction limit prevented light microscopy from being used to unveil details of cellular structure and function. In Neuroscience, the imaging of the synapse physical location represented by dendritic spines is affected by this limitation. We have recently described a method to apply Structured Illumination Microscopy (SIM), a super-resolution technique, to the detailed imaging of dendritic spined. The article, published in the video journal The Journal of Visualized Experiment (JoVE) is available here:

http://www.jove.com/video/51276/imaging-dendritic-spines-rat-primary-hippocampal-neurons-using

 

On May 22, 2014, I received the Top Paper Prize 2014, awarded by the Dutch Neurofederation. The award ceremony took place during the 2014 EndoNeuroPsycho Meeting in Lunteren. After accepting the prize in the name of all the paper's authors, I gave a plenary lecture discussing the main findings of the paper. 

The awarded paper was:

Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior.

Fitzsimons CP, van Hooijdonk LW, Schouten M, Zalachoras I, Brinks V, Zheng T, Schouten TG, Saaltink DJ, Dijkmans T, Steindler DA, Verhaagen J, Verbeek FJ, Lucassen PJ, de Kloet ER, Meijer OC, Karst H, Joels M, Oitzl MS, Vreugdenhil E.

Mol Psychiatry. 2013 Sep;18(9):993-1005. 

 

 For more details please see the Faculty of Sciences's News website at:

http://www.science.uva.nl/cms/nb/EN-2014-05-27 

 

Several factors, including epileptic seizures, can strongly stimulate ongoing neurogenesis in the adult hippocampus.

However, the exact role of the neurogenic response during epilepsy and its possible involvement in epileptogenesis have remained elusive.

In a recent article in The European Journal of Neuroscience, we discuss recent studies shedding new light on the interplay between epilepsy and neurogenesis.

The article is available here: 

• Article Bielefeld et al, The European Journal of Neuroscience, 2013

Recently, I gave some invited oral presentations in international scientific meetings:

The 2012 Meeting of the SFN:

 http://www.abstractsonline.com/Plan/SSResults.aspx

The 2013 Eurogenesis Meeting in Bordeaux

http://www.eurogenesis.com/

And the 2013 SENS meeting in Oviedo

http://www.senc2013.com/ponentes.html 

 

My  presentation at the last Abcam’s Meeting "Regulation of Adult Neurogenesis: From Epigenetics to Behavior", held on July 12-13th 2012 in Barcelona as satellite event to the 2012's FENS meeting, has been highlighted together with those From G. Kempermann, F. Gage and A. Fischer, in Epigenie, a blog dedicated to epigenetics news:

 http://epigenie.com/conferences/regulation-of-adult-neurogenesis-from-epigenetics-to-behavior/

 

 

We have recently published a new article in Molecular Psychiatry where we describe the role of the Glucocorticoid Receptor in the regulation of adult hippocampal neurogenesis and fear-motivated behavior:

 

• Article Fitzsimons et al Molecular Psychiatry 2013

Master internships available

 

 

We are looking for a very motivated and capable Master student (second internship preferably) to study the expression profile of the glucocorticoid receptor during neurogenesis from hippocampal stem cells .

Please contact me if you are interested

 

 

Previously on...

We were amongst the six finalist of the 2012's version of the Amsterdam Science Innovation Award (AMSIA). The AMSIA is a competition between researchers and students from the University of Amsterdam (UvA), the Academic Medical Centre (AMC), the Amsterdam Technical Highschool (HvA) and other research Institutes with innovative, originale and applicable ideas. We were honored to receive the Public's Award for the project "Modular Proteins as innovative non-viral vectors for gene therapy".   This project is a collaboration between the Fitzsimons' Lab and The Institute of Biotechnology and Biomedicine, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, University of Barcelona, Spain. 

Research Interests

Neural stem cells, hormones and microRNAs
Experiments at the laboratory are aimed at understanding the role of microRNAs and hormones in the generation of new neurons in the hippocampus. In doing so,we focus our work inutilizing RNA interference (RNAi) as a tool to study and treating neurologic diseases, such as epilepsy, depression and others, that may be related to chronic alterations in hippocampal neurogenesis.
We use a wide range of RNAi effectors from synthetic siRNAs to short hairpin RNAs and artificial microRNAs. In combination with viruses engineered and optimized to deliver RNAi effectors to stem cells and newborn neurons in the hippocampus in vivo, our experimental approach provides and excellent opportunity to contribute substantially to a currently booming scientific field.

Within this line of research, we are particularly interested in studying the interplay between microRNAs and hormone receptors in the regulation of neural stem cells in vitro and in vivo.

A central interest of the lab is the role of hormone receptors and microRNAs in the regulation of synaptic connectivity at the level of dendritic spines. With this aim we use state-of-the-art confocal microscopy techniques.

Nuclear receptor and G-protein coupled receptor signaling

A second part of the group's research focuses on understanding the molecular mechanisms involved in crosstalk between GPCRs and between GPCRs and nuclear receptors for hormones

Lab members

Carlos P. Fitzsimons, PhD, Group Leader
Marijn Schouten, BS, MS, PhD Student

Pascal Bielefeld, BS, MS, PhD Student

Ilse de Bruin

Luuk Picavet

Past: 

Diana Karina Alatriste, MS student 

Peter Roemers, MS student 

Joan Domingo-Espin, Guest PhD Student     
Renee Schreurs, BS, MS Student 
Erik van Heesbeen, BS, MS Student

 

Gideon Meerhoff, BS, MS, Lab. Assistant

 

Our viral vector production unit

Selected literature

A complete list of my publications could be found at http://publicationslist.org/c.fitzsimons
>Fitzsimons CP, van Hooijdonk LW, Schouten M, Zalachoras I, Brinks V, Zheng T, Schouten TG, Saaltink DJ, Dijkmans T, Steindler DA, Verhaagen J, Verbeek FJ, Lucassen PJ, de Kloet ER, Meijer OC, Karst H, Joels M, Oitzl MS, Vreugdenhil E. Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior. Mol Psychiatry. 2012 Aug 28. doi: 10.1038/mp.2012.123.  >Lucassen PJ, Fitzsimons CP, Korosi A, Joels M, Belzung C, Abrous DN. Stressing new neurons into depression? Mol Psychiatry. 2012 May 1. doi: 10.1038/mp.2012.39. >Lentivirus-mediated transgene delivery to the hippocampus reveals sub-field specific differences in expression.van Hooijdonk LW, Ichwan M, Dijkmans TF, Schouten TG, de Backer MW, Adan RA, Verbeek FJ, Vreugdenhil E, Fitzsimons CP. BMC Neurosci. 2009 Jan13;10:2.
>MicroRNA 18 and 124a down-regulate the glucocorticoid receptor: implications for glucocorticoid responsiveness in the brain. Vreugdenhil E, Verissimo CS, Mariman R, Kamphorst JT, Barbosa JS, Zweers T, Champagne DL, Schouten T, Meijer OC, de Kloet ER, Fitzsimons CP. Endocrinology . 2009 May;150(5):2220-8.
>The microtubule-associated protein doublecortin-like regulates the transport of the glucocorticoid receptor in neuronal progenitor cells. Fitzsimons CP, Ahmed S, Wittevrongel CF, Schouten TG, Dijkmans TF, Scheenen WJ, Schaaf MJ, de Kloet ER, Vreugdenhil E. Mol Endocrinol . 2008 Feb;22(2):248-62.
>Expression of a G protein-coupled receptor (GPCR) leads to attenuation of signaling by other GPCRs: experimental evidence for a spontaneous GPCR constitutive inactive form. Tubio MR, Fernandez N, Fitzsimons CP,Copsel S, Santiago S, Shayo C, Davio C, Monczor F. J Biol Chem . 2010 May 14;285(20):14990-8.
>Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein. Fitzsimons CP, Monczor F,Fernández N, Shayo C, Davio C. J Biol Chem . 2004 Aug 13;279(33):34431-9.

Past and ongoing collaborations

• Neus Ferrer and Joan Domingo-Espin. The Institute of Biotechnology and Biomedicine, Networking Centre on Bioengineering, Biomaterials and Nanomedicine,University of Barcelona, Spain.
• Paul Lucassen, Harm Krugers, SILS Center for Neurosciences, University of Amsterdam
• Marian Joels, Rudolf Magnus lab Utrecht and SILS, University of Amsterdam
• Ron de Kloet, Erno Vreugdenhil and Onno Meijer. Medical Pharmacology Department, LACDR, Leiden
• Davide de Petri-Tonelli, Department of Neuroscience and Brain Technologies,
  Italian Institute of Technology, Genoa, Italy.
• Federico Monczor, Laboratory of Receptor Pharmacology, Department of Medicinal Chemistry, Faculty of Biochemistry and Pharmacy, University of Buenos Aires, Argentina.
• Dennis Steindler, Department of Neuroscience, The McKnight Brain Institute,
  University of Florida College of Medicine.
• Connie Jimenez, OncoProteomics Laboratory, Dept. Medical Oncology, VUMC-Cancer Center Amsterdam
• Fons Verbeek, Section Imaging & BioInformatics, Leiden Institute of Advanced Computer Science
• Joost Verhaagen, Netherlands Institute of Neurosciences

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