Brain development and disease

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Group leader:  Alessandro Vercelli



Cross-talk between intrinsic and extrinsic mechanism in importin alpha 3 knock-out mice. Investigating the neurite outgrowth in embryonic neurons and the control gene regulation in importin alpha3 knock-out mice.
2022 - 2025 | Rita Levi Montalcini Fellowship, MUR, Italy

Letizia Marvaldi, head of research unit

Importins are proteins that shuttle information from the cytoplasm to the nucleus (Rishal and Fainzilber 2014). Importins are the gatekeepers of the nucleus, and as such can temporally coordinate transcriptional waves, for example as reported in importin alpha 3 knockout mice (Yousuf and Price 2020). Recently, we discovered that importins can control different functions, as importin alpha5 regulates anxiety behavior (Panayotis et al. 2018) while importin alpha3 controls acute and neuropathic pain (Marvaldi et al. 2020). We believe that there are different transcriptional programs in DRGs neurons that are responsible for distinct phases of neuropathic pain. Importin alpha3 knockout mice felt less acute and chronic pain due to a missed transport of c-FOS into the nucleus. After mapping the transcriptional changes in nociceptors induced by the loss of importin alpha 3, we were even able to mimic the analgesic effects of importin alpha3 loss with Sulmazole and Sulfamethizole (Marvaldi et al. 2020).

  • Neuropathic pain is caused by miswiring and abnormal organ targeting where excessive branching lead to more pain, we want to exploit if those phenotype is also due to a better regeneration and re-innervation of the target tissue. We will thoroughly mine for the transcriptional networks and key regulators that carry the signature of axonal growth.  Finally, we will compare our genes of interest with human neuropathic pain patients’ dataset to verify if these genes exert similar functions in humans. At the end we will look to potent drugs and therapeutic compounds.
  • We will discover the role of importin alpha 3 during development. We will determine the interaction of intrinsic factors (i.e.: importins) and extrinsic signals (i.e.: neurotrophin signaling) in patterning the phenotype of sensory neurons during development.

Iron arm with dementia: iron and mitochondria as new targets against Alzheimer's disease
2022-2024 | Fondazione Cassa di Risparmio di Torino (CRT)

Serena Stanga, head of research unit

Because of the increase ageing of the population, neurodegenerative diseases are dramatically incrementing; indeed, ageing is the main risk factor for dementia. The project aims to: i) unreveal new neurobiological mechanisms underpinning neurodegenreation, ii) identify new biomarkers able to predict cognitive decline and iii) new targtes for the development of drugs for Alzheimer's disease cure. We will study the mechanisms related to iron metabolism in the brain and specifically in the cerebral cortex and in the hippocampus, areas deeply touched by neurodegenerative processes.

3D bio-printing: neurobiology and engineering together to study and treat spinal cord injuries
2021-2023 | Fondazione CRT

Marina Boido, PI
co-PI Chiara Tonda-Turo (Politecnico of Torino)

In Piedmont, there are 4500 para- and tetraplegic patients. It is disabling disease, which completely upsets the life of patients. The spinal cord is the part of the central nervous system that connects the brain with the periphery: if due to an injury the spinal cord nerve fibers are damaged, this communication is interrupted and the results are dramatic (paralysis, loss of sensitivity, altered physiological functions). To date, there is no cure and patients are wheelchair-bound or immobilized in a bed, depending on the severity of the damage.

In this scenario, our ambitious project arises from the close collaboration between neurobiologists and engineers: we intend to exploit 3D bio-printing to build a three-dimensional cellular model of the spinal cord. This will allow us to replicate the anatomy of the spinal cord (healthy and injured) in vitro, letting us to study if and how nerve fibers degenerate and/or regenerate and to preliminarily test promising therapeutic strategies (such as the use of mesenchymal stem cells). Therefore, the project will have the dual purpose of creating a functional 3D cellular model of the spinal cord that will allowa first screening of drugs and therapies, and also will permits to reduce the use of experimental animals.

The role of SMN protein in translation: implications for Spinal Muscular Atrophy
2019-2022 | Fondazione Telethon

Marina Boido, head of research unit
Research network: coordinator Gabriella Viero, CNR, Trento

The aim of the project is to understand how alterations of SMN expression can affect translation (i.e. protein synthesis) in case of SMA. The study will be important not only to better understand the role of SMN (whose functions are only partially known) and the pathogenesis of the disease, but also to design innovative effective therapies to counteract this pathology.

Mental Health and urban Green/Blue
2018-2022 |  MIUR: Dipartimenti di Eccellenza  

Head of research unit: Alessandro Vercelli

Among the non-pharmacological methods for the prevention and treatment of diseases, the importance of man-nature interaction is increasingly emerging. Being in nature has a positive impact on blood pressure, cholesterol levels, stress reduction and can also stimulate the feeling of well-being and attention. Some of these positive effects are probably due to molecules released by plants in green areas: among these, terpenes - low molecular weight secondary lipophilic plant metabolites - are capable of influencing a wide range of biological activities in various models of human diseases.

In this project we evaluate how living in an urban environment close to green areas, and their frequentation, can reduce the depressive state and reduce the need for pharmacological drug consumption in depressed patients.

In collaboration with the Psychiatric Clinic (AziendaOspedalieraUniversitariaCittàdella Salute e dellaScienza di Torino - Presidio Molinette) directed by Prof. Rocca , we use a multimodal approach: we study the variations of biohumoral and epigenetic markers of inflammation and stress response, before and after chronic exposure to the "green". With fMRI we evaluate the effects of urban greenery exposure on brain connectivity.
At the same time, we study the biological effect of the exposure to urban greenery on the nervous system, to identify the phyto-molecules mediating these positive effects and their mechanisms of action in cell cultures.
The “forest bathing” and nature immersion could prove to be an easy-to-follow therapeutic indication, complementary to traditional drug therapies.

Development of combinatorial therapies for SMA
2019-2020 | AFM Telethon

Marina Boido, head of research unit
Research network: coordinator Ruben Artero, University of Valencia, Spagna; Cécile Martinat, I-STEM, Corbeil-Essonnes, France

In this project we will select and test in vitro and in vivo some FDA-approved drugs (alone or in combination), to provide the most efficient “cocktail” of therapeutics able to systemically increase SMN protein levels. Indeed we aim for discovery of an orally administered drug which will not only increase the SMN protein levels in motoneurons, but also in other affected tissues.

Mitochondria in Spinal Muscular Atrophy: dysfunctions and mitophagy
2018-2020 | Fondazione CRT - Richieste Ordinarie 2017

Marina Boido

The aim of the project is to deeply study mitochondria dysfunction and mitophagy in SMA. We intend to understand how the pathogenesis of SMA is linked to mitochondria alterations. The in-depth analysis of these aspects will contribute both to shed light on the complex mechanisms that cause SMA, but also to identify new therapeutic targets.

Identification of new druggable targets and potential therapeutic compounds for Spinal Muscular Atrophy, using a C.elegans model of neurodegeneration
2017-2020 | Fondazione Telethon

Alessandro Vercelli, head of research unit
Research network: coordinator Elia Di Schiavi, CNR, Napoli

The project will help us to identify new genetic partners interacting with SMN and to understand how they influence smn-1 dependent phenotypes; we also intend to identify new molecules able to prevent neurodegeneration caused by the lack of SMN.

My-AHA - My Active and Healthy Ageing
January 2016-2019 | Horizon 2020

Coordinator Alessandro Vercelli, NICO - University of Torino
The consortium is made of: Istituto Mario Boella (Torino), the Universities of Siegen and Koln (D), Loughborough (GB), Instituto de Biomecanica Valencia (E), Fraunhofer Portugal, Johanniter Austerreich (A), Kasa Solution (D), VitalinQ (N), GESMED (E). To the consortium participate as Extra-EU partners Seul National University (South Korea), Tohoku University (Japan), University of the Sunshine Coast (Australia), and the JIN company (Japan).

Aims and Relevance
The main aim of my-AHA is to reduce frailty risk by improving physical activity and cognitive function, psychological state, social resources, nutrition, sleep and overall well-being. It will empower older citizens to better manage their own health, resulting in healthcare cost savings. my-AHA will use state-of-the-art analytical concepts to provide new ways of health monitoring and disease prevention through individualized profiling and personalized recommendations, feedback and support.

An ICT-based platform will detect defined risks in the frailty domains early and accurately via non-stigmatising embedded sensors and data readily available in the daily living environment of older adults. When risk is detected, my-AHA will provide targeted ICT-based interventions with a scientific evidence base of efficacy, including vetted offerings from established providers of medical and AHA support. These interventions will follow an integrated approach to motivate users to participate in exercise, cognitively stimulating games and social networking to achieve long-term behavioural change, sustained by continued end user engagement with my-AHA.
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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.
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Motor neuron death in Spinal Muscular Atrophy (SMA): new animal models and innovative therapeutic strategies
2011-2015 | Italian Ministry of Health RF-2009-1475235

The proposed research project will aggregate: i) the Molecular Neuroanatomy and Pathogenesis Unit (G. Battaglia), at the IRCCS Foundation Neurological Institute "C. Besta" in Milano; ii) the Molecular and Computational Biology lab (F. Di Cunto) at the Molecular Biotechnology Center in Torino; iii) the C.elegans Neurobiology lab (E. Di Schiavi) at the Institute of Genetics and Biophysics of the CNR in Napoli; and iv) the lab of Developmental Neuroanatomy (A. Vercelli) at the NICO.

Spinal Muscular Atrophy or SMA is a severe autosomal recessive disease characterized by selective motor neuron degeneration. SMA is the leading genetic cause of infant mortality, with an incidence of 1:10.000 live births and an estimated carrier frequency of 1:35. The SMA determining gene was discovered in 1995 and termed survival motor neuron (SMN) gene.
The main protein product of the SMN1 gene, the FL-SMN protein, has its primary and most important role in spliceosomal assembly and pre-mRNAs maturation. However, how reduced FL-SMN levels lead to selective degeneration of motor neurons in SMA still remains elusive. Accordingly, no effective therapy is up to now available for affected children.
A novel, truncated isoform of the FL-SMN protein, a-SMN or axonal SMN, with selective expression in the axons of spinal cord motor neurons, has been recently reported by our group. We intend to verify the in vivo function and therapeutic properties of the FL-SMN and a-SMN proteins in both invertebrate and mammalian experimental settings.

Generation of authentic human striatal neurons from pluripotent stem cells for transplantation in Huntington's disease
2013-January 2016 | PRIN - Italian Ministry of University and Research

Coordinator: Elena Cattaneo; Head of local research unit: Alessandro Vercelli
Research Network: Biella Gerardo Rosario, University of Pavia; Biunno Ida, Cnr; Moresco Rosa Maria, University Milano-Bicocca

The anatomy of the striatum in mammals is characterized by medium-sized spiny GABAergic projection neurons and by 5% interneurons. On immunohistochemical and histochemical grounds, the striatum can be subdivided in lightly labeled striosomes and an intensely labeled matrix, in which neurons are differentially organized. The striatum is part of neural circuits which play a role in motor behavior and in the mechanisms of reward. The anatomical organization is completely disrupted  in Huntington's disease, where projection neurons degenerate massively, causing a secondary neuronal death in the substantia nigra, to which the striatum is strongly interconnected.

The aim of the consortium is to explore the potential for a specific set of stem cells, human ventral striatal progenitors, derived from embryonic stem cells, to  replace lost projection neurons in a rat experimental model of Huntington's  disease.
In the frame of this project, UNITO will be responsible for studying the anatomical integration of stem cells in the striatum. The results obtained by our UNIT will be compared with those obtained in the same animals on motor behavior in order to correlate improvement in motor performance with the proper differentiation of stem cells and their integration into neural circuits.

Use of biomimetic scaffolds and stem cells to support the regeneration of the injured spinal cord
2014-2016 | Fondazione CRT

Marina Boido, NICO co-PI with Gianluca Ciardelli e Chiara Tonda-Turo, Politecnico di Torino

The project derives from a collaboration between UNITO and POLITO. In the project we employ hydrogels (biomimetic polyurethanes, water-soluble and heat-sensitive) in which stem cells (embryonic or adult) are encapsulated. The scaffolds are tested in vitro, in order to assess their ability to host the cells.
Moreover we aim to inject scaffolds and stem cells in vivo, in a mouse model of spinal cord contusion. To evaluate the efficacy of the treatment, we intend to study sensorimotor performance of animals, the survival/integration of cells in the host tissue, and the expression of molecules involved in the regeneration and neuroinflammation.