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Fabrizia Cesca

Affiliated Researcher
Researcher

Contacts

Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, L.go Rosanna Benzi, 10
+39 010 5558 382
Contact Me

About

I obtained a Master's degree summa cum laude in Biological Sciences at the University of Padua. After my degree I moved to London, where I attained a PhD in biochemistry at the University College of London, working in the laboratory of Dr. Schiavo at Cancer Research UK. I then moved to IIT, in Genova, where I currently hold a Researcher position in the group led by Dr. Benfenati.


I have spent most of my career working in the neuroscience field. During my PhD and postdoc, I have worked on axonal transport, intracellular trafficking and signaling, mouse genetics and development, physiology of neurotrophins, and synaptic vesicle recycling. I have recently approached the new and exciting field of optogenetics, and I am now supervising a number of projects dealing with the development and validation of new optogenetic probes for in vitro and in vivo applications. In addition, I am involved in a number of collaborative projects, all EU-funded, aimed at characterizing new biocompatible materials for nervous system regeneration.

Projects

My past and present research activity within the IIT Center for Synaptic Neuroscience (IIT-NSYN) has focused on the understanding of the molecular and genetic pathways controlling neuronal development and maturation, as well as on the mechanisms that ensure the maintenance of network homeostasis. I have approached this topic by studying (i) the biology of the neurotrophin family of growth factors, mainly brain-derived neurotrophic factor (BDNF), and (ii) the role of the RE1-silencing transcription factor (REST) in the control of gene expression through epigenetic modifications of target chromatin. More recently, I have approached the field of ‘material biology’ (iii), working on the characterization of novel biocompatible materials to modulate network development and activity and drive nervous system regeneration.

       (i) In a series of papers spanning several years of research, I have characterized the role played by Kinase D interacting substrate of 220 kDa (Kidins220), a transmembrane neuronal protein, in the modulation of the intracellular signaling pathways triggered by neurotrophins. In vitro studies on primary neurons and astrocytes showed that Kidins220 mediates BDNF stimuli to achieve proper growth, differentiation and maturation of neural cells, modulating important physiological processes such as intracellular trafficking, synaptic activity and intracellular Ca2+ dynamics. In parallel to this work, I have also undertaken an in vivo approach, using Kidins220-deficient mouse lines that I generated at UCL, which allowed investigating how Kidins220 and neurotrophins contribute to nervous system development and to the acquisition and maintenance of higher functions such as learning, memory and social behavior. In the latest years, I have worked on this project together with two PhD students and a post-doctoral fellow, hired thanks to a ‘Compagnia di San Paolo’ grant I was awarded, all of whom I directly supervised. By working on this research line, I have gained an extensive knowledge of cellular neurobiology, especially on the molecular mechanisms modulating neuronal survival, growth and differentiation. Moreover, I have acquired a broad expertise in the phenotypic analysis of transgenic mouse lines, mastering a number of experimental approaches including biochemistry, histology and behavioral analysis.

       (ii) The alteration of REST-dependent transcriptional regulation is a common feature of several neurological diseases, thus, the possibility to manipulate the activity of this transcription factor is of high interest for pre-clinical and clinical studies. To tackle this challenge, I contributed to the engineering of two classes of optogenetic tools able to bi-directionally modulate the activity of REST: probes based on the light-sensitive Light-Oxygen-Voltage (LOV) domain, to inhibit REST binding to target genes, and probes based on the RNA-binding protein Pumilio and FBF (PUF), to increase REST expression and activity (unpublished). These tools are currently applied to understand the role of REST in the control of neuronal excitability and synaptic plasticity, in vitro and in vivo in pharmacological and genetic models of epilepsy and multiple sclerosis (MS), as well as by using a transgenic mouse line bearing the floxed REST gene. We are furthermore studying the signaling pathways and post-translational modifications controlling REST activity. Co-leading this project gave me the opportunity to approach the field of optogenetics, and to acquire the basic mechanisms underlying the light-induced modulation of cell physiology. Moreover, thanks to the ongoing collaboration with the research group led by Prof. Uccelli (IRCCS San Martino, Genova), I became familiar with the mouse model of experimental autoimmune encephalomyelitis (EAE), a widely accepted model of demyelinating diseases, such as MS. This allowed me to gain some experience on the important topic of neuroinflammation, which I am currently pursuing through the use of neuronal cultures in vitro, and in vivo in EAE mice.

            (iii) Research on novel biocompatible materials has blossomed in recent years, especially for applications in the neuroscience field, as there is a paucity of effective treatments to recover neuronal damage upon insults or in the presence of neurodegenerative diseases. In this context, I carried on my research activity mainly within a number of EU-funded projects, including the GRAPHENE Flagship. With the aim of identifying novel materials suitable for drug delivery, I contributed to the characterization of the toxicity of a range of graphene-based materials and nanoparticles, with primary neurons, astrocytes and microglia [Chiacchiaretta et al, under revision]. Particular attention is presently devoted to the ability of these materials to efficiently and safely cross the blood-brain barrier (BBB) to act as efficient vectors for drug or nucleic acid delivery to the brain. In parallel, we are investigating the possibility to grow functional neural networks on 2D planar / 3D scaffolds made of electrically conductive materials, patterned and functionalized with various bioactive molecules. Conductive materials are of interest as they can drive growth and regeneration, while adhesion and synaptogenic molecules can be exploited to achieve patterned growth and enhance the formation of functional synapses. The performance of the various substrates is evaluated first in vitro, and the best-performing devices are subsequently tested in vivo, in animal models of nervous system injury.

Selected Publications

Bramini M, Sacchetti S, Armirotti A, Rocchi A, Vázquez E, León Castellanos V, Bandiera T, Cesca F*, Benfenati F*: Graphene Oxide Nanosheets Disrupt Lipid Composition, Ca(2+) Homeostasis, and Synaptic Transmission in Primary Cortical Neurons. ACS Nano. 2016 Jul 26;10(7):7154-71. *equal contribution, corresponding authors

Paonessa F, Criscuolo S, Sacchetti S, Amoroso D, Scarongella H, Pecoraro Bisogni F, Carminati E, Pruzzo G, Maragliano L, Cesca F*, Benfenati F*: Regulation of neural gene transcription by optogenetic inhibition of the RE1-Silencing Transcription Factor. Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):E91-E100. doi: 10.1073/pnas.1507355112. Epub 2015 Dec 23. *equal contribution, corresponding authors

Fiala GJ, Janowska I, Prutek F, Hobeika E, Satapathy A, Sprenger A, Plum T, Seidl M, Dengjel J, Reth M, Cesca F, Brummer T, Minguet S, Schamel WW: Kidins220/ARMS binds to the B cell antigen receptor and regulates B cell development and activation. J Exp Med. 2015 Aug 31. pii: jem.20141271

Medrihan L, Cesca F, Raimondi A, Lignani G, Baldelli P and Benfenati F: Synapsin II desynchronizes neurotransmitter release at inhibitory synapses by interacting with presynaptic calcium channels. Nat Commun. 2013;4:1512

Cesca F*#, Yabe A*, Spencer-Dene B, Scholz-Starke J, Medrihan L, Maden CH, Gerhardt H, Orriss IR, Baldelli P, Al-Qatari M, Koltzenburg M, Adams RH, Benfenati F and Schiavo G: Kidins220/ARMS mediates the integration of the neurotrophin and VEGF pathways in the vascular and nervous systems. Cell Death Differ. 2012 Feb;19(2):194-208 #corresponding author

 

Awards

Principal Investigator in the following project:

  • Compagnia di San Paolo (Italy) “Novel modulators of sodium channels and neuronal excitability” 2014-2015

Co-investigator in the following projects (past and present):

  • Compagnia di San Paolo “New molecularly targeted therapies for metastatic Uveal Melanoma” 2018-2020 [Principal Investigator: Dr. U. Pfeffer, Ospedale Policlinico San Martino, Genova]
  • Compagnia di San Paolo “Modulation of adult visual cortical plasticity via optogenetic control of gene expression” 2015-2017 [Principal Investigator: Dr. F. Maya-Vetencourt, IIT Genova]
  • PROGETTI GIOVANI RICERCATORI - Italian Ministry of Health “Study of the role of extracellular vesicles in promoting myogenic differentiation” 2014-2016 [Principal Investigator: Dr. M. Guescini, University of Urbino]
  • PRIN-MIUR - Italian Ministry of University and Research “Spinal injury: towards the development of cell-instructive scaffolds for nerve tissue repair” 2014-2016 [Principal Investigator: Prof. L. Ballerini, University of Trieste / SISSA]
  • CURE - Citizens United for Research in Epilepsy (U.S.) “Optogenetic regulation of the transcription of epilepsy genes: an innovative strategy to cure drug-resistant epilepsy” 2014 [Principal Investigator: Prof. F. Benfenati, IIT Genova]

Part of the Research team in the following projects (past and present):

  • “GRAPHENE” (Graphene-Driven Revolutions in ICT and Beyond, ICT Call FET Flagships 2013, FP7-ICT-2013-FET-F), 2013-2016 Ramp-up phase, WP2 ‘Health and environment’; 2016-2018 Core 1 and 2018-2020 Core 2, WP4 ‘Health and environment’ [Principal Investigator: Prof. F. Benfenati, IIT Genova]
  • FISM “Therapeutic targeting of REST activity and expression to reduce neurodegeneration and synaptic deficits in chronic EAE” 2016-2018 [Principal Investigator: Prof. A. Uccelli, University of Genova]
  • “DESIRE” (Development and Epilepsy - Strategies for Innovative Research to improve diagnosis, prevention and treatment in children with difficult to treat Epilepsy, FP7-HEALTH-2013-INNOVATION-1), 2013-2017 [Principal Investigator: Prof. F. Benfenati, IIT Genova]
  • “NEUROSCAFFOLDS” (Rapid prototyping scaffolds for the nervous system, FP7-NMP-2013-EU-China), 2013-2015 [Principal Investigator: Prof. F. Benfenati, IIT Genova]
  • “OLIMPIA” (Training Network on Organic Optoelectronics Integrated with Living Systems for Neuroscience Investigations and Applications, FP7-PEOPLE-2012-ITN), 2012-2015 [Principal Investigator: Prof. F. Benfenati, IIT Genova]
  • “FOCUS” (Single Molecule Activation and Computing, ICT-2009 8.7 FET proactive 7: Molecular Scale Devices and Systems), 2011-2013 [Principal Investigator: Prof. F. Benfenati, IIT Genova]

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