Group leader: Annalisa Buffo
Projects
Role of interleukin 6 in the pathogenesis of Rett syndrome: focus on astrocyte-neuron crosstalk and its therapeutic implication
PRIN-PNRR 2022 MUR Ministry of University and Research
PI: Angelisa Frasca, University of Milan; co-PI: Enrica Boda
Rett syndrome (RTT) is a severe neurodevelopmental disorder, representing the first cause of intellectual disability in girls worldwide. The limited knowledge of RTT pathogenesis represents an obstacle for the development of rationale-based experimental therapies. Although initial studies supported the exclusive involvement of neurons, recent data indicated that astrocytes contribute to RTT pathogenesis through non-cell autonomous mechanisms. As synaptic defects represent a hallmark of RTT, in this project, we will investigate the mechanisms underlying the negative effect exerted by RTT astrocytes on the formation and maintenance of neuronal synapses. To this aim, we will exploit astrocytes and cortical neurons generated from human induced pluripotent stem cells (iPSCs) obtained from RTT patients
Targeting glial cell dysfunctions to treat cognitive defects and epilepsy in primary autosomal recessive microcephaly-17 (MCPH17) models
2023 - 2025 | PRIN - MUR Ministry of University and Research
Enrica Boda, PI
In this project, we propose a combination of experimental and pharmacological approaches aimed at correcting the dysfunctions of microglial cells, in order to support the maturation and function of nervous circuits in autosomal recessive primary microcephaly type 17 (MCPH17) models. The ultimate aim of the research is to propose a new therapeutic option - based on the targeting of glial cells and not of neurons - for patients with MCPH17. The project also involves the Research Unit of Dr. Eleonora Vannini at the Neuroscience Institute of the CNR in Pisa.
In vitro and in vivo molecular mapping of cell therapy for Huntington Disease at single-cell resolution
2023 - 2025 | PRIN - MUR Ministry of University and Research
Annalisa Buffo, PI
Huntington’s disease (HD) is a neurodegenerative disorder that compromises motor and cognitive functions as a consequence of the prominent loss of striatal Medium Spiny Neurons (MSNs). To restore the lost functions and ensure long-term therapeutic effect, newly transplanted neurons must fully qualify as MSNs and must establish appropriate functional connections after transplantation. In this project we aim to define the identity of the most therapeutic cells derived from human embryonic stem cells for effective cell replacement in HD. Towards this goal, in collaboration with prof. Elena Cattaneo (University of Milan), we will use advanced in vivo lineage tracing in combination with transcriptional profiling of the grafted neurons that integrate in the host brain and rewire lost circuits.
Targeting oligodendroglial cell dysfunctions to treat cognitive defects and epilepsy in primary autosomal recessive microcephaly-17 (MCPH17) models
2023 - 2025 | Telethon Foundation
Enrica Boda, PI
In this project we aim at targeting oligodendroglia and myelin dysfunctions in primary recessive autosomal microcephaly 17 (MCPH17) models, as an option to sustain neuronal/circuitries maturation and function, resulting in a beneficial effect on the functional outcome of MCPH17 models.
SPACER: a single cell SPAtiotemporal transcriptomic atlas to unveil CERebellar development and function
January - June 2023 | Banca d'Italia
A Buffo, V Cerrato, PI
Our research team will conduct single-cell gene expression analyses on human fetal tissues. Our goal is to investigate the development of cerebellar cells in humans. These investigations will complement prior studies conducted in mice ( grant Fondazione Veronesi and EASI genomics ), providing a comprehensive understanding of cerebellar development and function in both species. This knowledge holds significant relevance for potential translational applications in clinical research for human health.
Air pollution and Multiple Sclerosis: effects of the exposure to particulate matter (PM) on neuroinflammation and myelin repair.
2021-2023 | Cassa di Risparmio di Torino (CRT) Foundation
Enrica Boda, PI
In this project we will study the mechanisms underlying the negative effects of exposure to environmental particulate matter (PM) in myelin repair ( Air pollution and Multiple Sclerosis ) and the higher vulnerability to PM of subjects primed to develop autoimmunity against myelin.
SPACER: a single cell SPAtiotemporal transcriptomic atlas to unveil CERebellar development and function in mouse
2021-2022 |
EASI Genomics 3
rd
call for Proposals for Transnational Access Projects 2021
A. Buffo, V. Cerrato
Thanks to this support, our researchers will perform
in situ
gene expression analyses on rodent tissues at distinct developmental stages before and after birth. In this way, we will study the molecular processes underneath the generation and physiology of cerebellar cells, aiming at fully clarifying the mechanisms of functioning and misfunctioning of this brain area. The experiments funded by EASI Genomics will be performed in Stockholm, in a prestigious facility partner of the consortium, named SciLife Lab.
> read more
Pilot Project: Air pollution and Multiple Sclerosis: role of particulate matter (PM) exposure and associated extracellular vesicle trafficking in neuroinflammation and demyelination.
2020-2021 | Italian Multiple Sclerosis Foundation (FISM)
Enrica Boda, PI
Research network: Valentina Bollati, Antonello Rigamonti (University of Milan)
In this project, we will investigate the role of particulate matter exposure as risk factor for the onset and progression of Multiple Sclerosis and the undelying cellular mechanisms
Novel Strategies for Cell-based Neural Reconstruction -
NSC-Reconstruct
2020-2024 | H2020-SC1-BHC-2018-2020
Research network: Elena Cattaneo, Coordinator (University of Milano), Malin Parmar (University of Lund), Oliver Bruestle (UniversitaetsKlinikum Bonn), Ernest Arenas (Karolinska Institutet), Roger Barker (University of Cambridge), Agnete Kirkeby (Kobenhavns Universitet), Meng Li (Cardiff University), Magdalena Goetz (Helmholtz Zentrum Muenchen), Pierre Vanderhaeghen (VIB-KULeuven Center) , Andreas Bosio (Miltenyi Biotec GMBH), Simone Haupt (Life and Brain GMBH), Carlos Villaescusas (Novo Nordisk).
In this project we will be leading WP3 and specifically aim at developing innovative therapeutic approaches for Huntington Disease (HD) based on the transplantation of human stem cell derivatives in preclinical models of HD and on training protocols to favour the integration of the transplanted cells. Further, we will implement strategies of in situ reprogramming to obtain striatal neurons from glial cells, and investigate the mechanisms regulating reactivity and activation of a neurogenic potential in astrocytes.
Oligodendrocyte Precursor Cells for Myelin Repair and Gliomagenesis
2019-2021 | Progetti di ricerca ex-post di Ateneo (University of Torino and Compagnia di San Paolo)
A.Buffo, E. Boda
This project was conceived as part of an european ITN-ETN grant application coordinated by Fernando de Castro, Cajal Institute, Madrid. In this frame, this local funding supports our studies on the functional heterogeneity of oligodendrocyte precursor cells in response to DNA damage and oxidative stress which occur in multiple CNS pathologies and dysfunctions, from Multiple Sclerosis to chemotherapy.
Allele-specific siRNAs as therapeutic option for ADLD: in vitro pre-clinical validation on unique human experimental models
2020-2022 | ELA International, Luxembourg
Research network: E. Giorgio and A. Brusco (University of Torino), S Goldman (University of Rochester, USA).
In this project we will generate two innovative glial in vitro disease models based on induced pluripotent stem cells (iPSC) derived from ADLD (Autosomal Dominant leukodystrophy with autonomic disease) patients that will allow validating our therapeutic strategy based on Allele Specific Silencing. Our project is intended to pave the way towards a therapy for ADLD and also establish distinctive human ADLD-relevant models and therapeutic approaches that may have great importance for future studies non only on ADLD but also on the physiopathology and therapy of other leukodystrophies and genetic diseases.
Driving microglia metabolism toward remyelination and restoration of brain damage in MS
2015-2018 | Merck Serono/Grant for Multiple Sclerosis Innovation
Annalisa Buffo, head of research unit
Research network: coordinator Claudia Verderio, Neuroscience Institute (IN) of CNR, Marta Fumagalli, University of Milan, Pierre Gressens, Inserm, Paris; Peter Cameliet, Vesalius Research CentreLeuven; Antonio Uccelli, University of Genoa
This project aims at defining the metabolic signatures that define a pro-regenerative microglial phenotype as expressed by extracellular-vescicle-mediated enhancement of remyelination by rodent oligodendrocyte progenitor cells. The ultimate goal of this research is to modulate the phenotype of human microglia so that microglia can foster myelin repair. We contribute our specific expertise in oligodendrocyte progenitors and mouse models of Multiple Sclerosis and examine how delivery of microglia-derived extracellular vescicle to the brain of mouse models affects oligodendrocyte progenitors and remyelination in vivo.
Characterization of a novel microRNA involved in myelination: a new potential pathogenetic mechanisms in multiple sclerosis
2015-2017 | Cariplo Foundation - Biomedical Research conducted by Young Researchers
Enrica Boda, head of reseach unit; Davide Lecca, University of Milan, coordinator
This project aims at elucidating the role of a novel family of miRNAs in the regulation of oligodendroglial differentiation and in the pathogenesis of Multiple Sclerosis.
Influence of maternal behaviour on the expression of brain plasticity brakes: a role in the susceptibility to anxiety?
2015-2017 | Research Project, University of Turin - Compagnia di San Paolo
Daniela Carulli co-PI with Carola Eva, NICO
This project aims at elucidating whether maternal care affects chemical/physical features of perineuronal nets in the limbic system thereby influencing neuronal communication within specific networks and, in turn, anxiety in the adult.
Neurostemcellrepair - European stem cell consortium for neural cell replacement, reprogramming and functional brain repair
2013-2017 | FP7 European Union
E Fucà, A Buffo, D Carulli participating in the research unit headed by A Vercelli;
Research network: Elena Cattaneo, University of Milan, coordinator, Ernest Arenas, Karoliska Institute, deputy coordinator, Parmar Malin, University of Lund, Stephen Dunnet, University of Cardiff, Oliver Brustle, University of Bonn, Roger Barker, University of Cambridge, Charles ffrench-Constant, University of Edimburgh, Andreas Bosio, Milteny, Ida Biunno, Isenet).
This project aims at developing new strategies for stem cell therapies in Hungtington and Parkinson diseases, including acquisition of specific neuronal identities and functional integration in the recipient brain. We contribute our expertise in rodent models of Hungtington disease, and analyse how specific training activities can ameliorate differentiation and integration of grafted cells.
more information > www.neurostemcellrepair.org
Determinants of neuronal degeneration in Ataxia-Telangiectasia
2014-2017 | Telethon Foundation
Project PIs: Domenico Delia, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Lorenzo Magrassi, Dipartimento di Scienze Clinico-Chirurgiche, Diagnostiche e Pediatriche, University of Pavia. Annalisa Buffo and Giulia Nato take part in the project as external collaborators.
This project aims at unveiling the functional defects that determine malfunctioning and neurodegeneration in the cerebellum of patients suffering from Ataxia-Telangiectasia. To reach this goal we study how neuronal cells obtained from the fibroblasts of patients and healthy controls mature, survive and function.
Endogenous sources of stem cells/ neural progenitors for CNS repair
2014-September 2016 | Fondazione CRT
Annalisa Buffo co-proponent with Luca Bonfanti and Paolo Peretto, NICO
This project aims at investigating the physiology of parenchymal progenitors and their gliogenic and neurogenic responses upon lesion. Based on our specific expertise, we investigate dedifferentiation/reprogramming in reactive astrocytes and the properties of oligodendrocyte progenitors.
Targeting oligodendrocyte progenitor cell division mode to improve myelin repair in the aging CNS
2014-2015 | Fondazione Umberto Veronesi - Postdoctoral Fellowship Program, Enrica Boda
Myelin is a lipid-rich ensheathment produced by specialized cells called oligodendrocytes, that enwrap neuronal axons and allow the fast conduction of nervous signals. Myelin damage causes very serious pathologies characterized by motor and cognitive symptoms. In the human brain, aging is associated with the loss of myelin, reduced oligodendrocyte production and delayed remyelination in case of insults or pathology.
This is at least in part due to molecular alterations in oligodendrocyte progenitors, that affect their division modality and regenerative/reparative functions. The identification of these molecular mechanisms is highly relevant for the comprehension of the OPC biology and age-related functional decline, and can set the basis for new therapeutical approaches aimed at improving adult oligodendrogenesis and eventually ameliorate myelin integrity and repair at old ages.
This knowledge may be also applied to the study and treatment of human neurodegenerative diseases.
Complex mechanisms underlying permanent effects of the perinatal environment on neural plasticity and vulnerability to psychopathology
2014-2015 | Fondazione CRT
D. Carulli and A. Buffo: co-PI with Carola Eva, NICO
This project aims at investigating whether maternal care has an impact on the development of perineuronal nets and myelin in the limbic system, in parallel with an alteration of emotional behavior of adult mice.
Effect of substances of abuse, psychoactive drugs, stress and maternal care on brain development and vulnerability to psychopathology
2010-2012 | PRIN2010 Italian Ministry of University and Research, N. 20107MSMA4
A Buffo, head of Unit, participant: D Carulli; Giovanni Biggio, University of Cagliari, coordinator;
Marco Riva, University of Milan, Carola Eva, University of Turin, Paola Palanza, University of Parma, Nicoletta Brunello, University of Modena.
This project examines how perinatal adverse events, known to be associated with vulnerability to the onset of psychopathology and behaviour disorders, affect the normal progression of myelination and the deposition of plasticity brakes. We contribute our expertise on oligodendrocytes, myelin and perineuronal nets.