Individuation of the S100b Protein as a Therapeutic Target in Multiple Sclerosis Pathogenic Processes

Project location: ITALY, Rome
Project start date: September 2019 - Project end date: October 2021
Project number: 2019-041
Beneficiary: Università Cattolica del Sacro Cuore

Università Cattolica del Sacro Cuore (UCSC) (, founded in 1921, includes 5 campuses (Milano, Brescia, Piacenza, Cremona, Roma) and 14 faculties, covering the understanding and study of those topics that have proved vital to the well-being of each human being: the new frontiers of economics, bioethics, environmental recuperation, developments in the judicial fields, family dynamics, major mass phenomena, the evolution of political systems, new horizons in medicine, the technological applications of physics and mathematics, and the most recent discoveries in environmental research. The School of Medicine at the Rome Campus (from 1961) is at present a world-class training ground for future leaders in medical research and practice - including every modern medical discipline as well as some of the most respected medical scholars all over the world - public health, and biomedical science.
The University plays a pivotal role in the Italian community through the Medical School with the research/ teaching hospital Fondazione Policlinico Universitario Agostino Gemelli IRCCS (FPG)(, that represents almost 10% of the entire productive capacity of the Lazio Regional Health Service with almost 100,000 patients cared every year. It is the second largest hospital in Italy, the largest hospital in Rome and one of the largest private hospitals in Europe.The hospital staff includes more than 5,000 employees, of whom almost 1000 physicians and more than 2,000 nurses. As of 1 August 2015 the Hospital demerged from UCSC and in November 2015 it has also taken over the management of the Complesso Integrato Columbus, a treatment and rehabilitation centre close to the Hospital. In 2018 Fondazione Policlinico Universitario Agostino Gemelli has been recognised by the Italian Ministry of Health as IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico – Institute of Research and Care) for the disciplines of "Personalised Medicine" and "Innovative biotechnologies" (ministerial decree of 28 February 2018 published on G.U n. 81 of 07 April 2018). IRCCSs are organisations of particular national interest as they combine the healthcare activity with clinical and translational research, in order to develop new advanced therapies and treatments for patients. The Ministry of Health places strict restrictions on the assignment of the recognition as IRCCS: in Italy only 51 Institutes have proved to have the requisites necessary to be assigned this status. Within the Italian national scenario the Policlinico Gemelli is one of the most relevant IRCCSs for number of patients and health services provided both at regional level and at national and international level, as well as for the numerous high level international collaborations for the development of new therapies and devices for the treatment and improvement of patients' quality of life. 
UCSC has a longstanding expertise in the management of National and International research projects, also originated from the mentioned strict connection with the Policlinico Gemelli, with an annual turnover from Research activities of approximately 30mln euro per year (30.092.682 in 2016, 29.662.578€ in 2017). In the last 10 years UCSC has managed 138 EU funded research projects, both as coordinator and as beneficiary.
In 2018 the School of Medicine and surgery of Università Cattolica del Sacro Cuore, together with the Fondazione Policlinico Universitario A. Gemelli IRCCS, has received more than 22 mln € of funding for research from public and private profit and no-profit entities.
This collaborative study involves the Institute of Anatomy and Cell Biology (UCSC), the Institute of General Pathology (UCSC), the CNR-ICRM Institute of “Chimica del Riconoscimento Molecolare”, based at UCSC, and the CNR Institute of Cell Biology and Neurobiology, hosted at UCSC. These laboratories are fully equipped for most advanced molecular/cell biology and immunocytochemistry studies. A fully equipped animal house is also available at UCSC. The proximity with the Policlinico Universitario A.Gemelli is the premise for a prompt translational application of research findings obtained. 
The Principal Investigator (PI) of this project is Prof Fabrizio Michetti (1970 MD; 1974 Neurologist; 1977 Psychiatrist, UCSC. Web of Science: H index 39, more than 4,900 citations). Prof Michetti is currently Contract Professor for Neuroanatomy at the UCSC Medical School, as well as Contract Professor for Human Morphology at the Università Vita Salute San Raffaele Scientific Institute, Milan (since 2016) having been the Chairman of the Institute of Anatomy and Cell Biology of UCSC (1999/2016) where currently he carries out research activities. He is the author of 164 papers published in full in international scientific journals (including Nature, The Lancet). Personal Impact Factor:680. He is the applicant of an EU/USA granted patent. His main scientific interests focus on the evaluation of biomarkers and active factors in neural injury, with special reference to the S100B protein (authorship in 91 publications on this topic) and, in particular, showed for the first time the increase of S100B levels  in biological fluids of MS patients as an index of active phase of the disease (5). Prof Francesco Ria (Associate Professor of General Pathology at the UCSC Medical School) is an internationally recognized neuroimmunologist especially expert in RR-EAE studies and, with the collaboration of Dr Mariagrazia Valentini (Research Fellow at the Institute of General Pathology, UCSC Medical School) will induce the RR-EAE model in SJL mice, will administer treatments and will score clinical signs and symptoms (CSS) as described in the study design. Dr Maria Elisabetta Clementi and Dr Beatrice Sampaolese (Senior Researcher and Technologist at the CNR- Institute of “Chimica del Riconoscimento Molecolare”, respectively) are internationally recognized  investigators mainly involved in the study of inflammatory/oxidative mediators, including S100B, and will perform biomolecular determinations on tissues under investigation as described in the study design. Dr Cinzia Volonté (…at the CNR- Institute of “Biologia Cellulare e Neurobiologia”) and Dr Susanna Amadio (…at the Cellular Neurobiology Unit, Santa Lucia Foundation IRCCS, Rome) are internationally recognized investigators mainly involved in the study of neuroinflammatory processes, including MS, and will perform morphological/immunohistochemical determinations on tissues under investigation, as described in the study design.   

MS is an autoimmune disease now recognized as a global disease, affecting more than 2.3 million persons worldwide , with an occurrence especially high in Western Europe and North America (for review,1),  The pathologic hallmarks of the disease are demyelination and axonal loss, characterized by focal lesions/plaques which are scattered throughout the white matter of the central nervous system (CNS); these plaques contain a combination of pathologic lesions,including edema, inflammation, gliosis, demyelination and/or axonal loss. A variety of pathogenic processes have been implicated in plaque formation, including oxidative stress promoted by macrophages/microglia,neurotoxic factors secreted by activated T cells, and autoantibodies directed at self-antigens. However, the precise mechanisms leading to inflammation are largely unknown; hence, the identification of such factors would be essential to develop target therapeutic strategies for the disease (for review,2).

This project, which received a grant from the Nando and Elsa Peretti Foundation, aims at significantly participating in the promotion of physical and mental health of the large number of persons affected by the disease.

S100B is a calcium/zinc-binding protein secreted by mature astrocytes, associated, at high levels, with nervous tissue injury in a variety of neuropathological processes, including Multiple Sclerosis in the acute phase. An increased expression of S100B has been observed in acute demyelination and chronic active MS lesions. UCSC proposes to test in vivo the hypothesis that S100B is a promoting factor in MS pathogenesis, interfering with its synthesis or action, may have beneficial effects on disease onset and progression. UCSC proposes to explore in in vivo model of relapsing remitting experimental autoimmune encephalomyelitis. Inhibition of S100B activity will be obtained by administration of pentamidine, which is known to block the S100B action, an antiprotozoal drug and arundic acid, which inhibits S100B synthesis in astrocytes. UCSC expects that inhibition of S100B, obtained by antagonizing S100B action, may ameliorate the progression of the disease in mice where MS has been induced.

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