Dottorato in BIOLOGIA CELLULARE E DELLO SVILUPPO

email: loretta.tuosto@uniroma1.it
telefono: +390649917584
edificio: RM024
stanza: A12

PERSONAL STATEMENT: Our research activity has been focused in the fields of cellular and molecular immunology and oncology. Our work has resulted in the development of a well-characterized system to analyze the molecules, mechanisms and signal transduction pathways involved in cell activation and apoptosis. The analysis of apoptosis induction was initiated in 1993 and allowed the clarification of signals regulating the susceptibility of T cells to apoptosis induced by several stimuli, including immunosuppressive drugs and HIV-1. My studies unraveled the role of Bcl-2 family proteins in regulating T lymphocyte cell death in response to specific apoptotic signals.
Our laboratory also characterized the signalling pathways regulating mitochondria-dependent and Bax-regulated apoptosis in response to chemotherapeutic drugs. These studies contributed to elucidate and the role of p53 and p73 oncosuppressors in the acquisition of resistance to apoptosis by tumour cells. In particular, we identified a new tumour-associated mutant of p53 (K351N) involved in the acquisition of resistance to apoptosis in ovarian cancer cells and with specific defects in tetramerization, transcriptional activity and nuclear export.
We also contributed to the characterization of the molecules involved in the activation of NF-kB signalling in T lymphocytes. We were among the first to evidence that the engagement of CD28 costimulatory molecule activates in primary T lymphocytes a non-canonical NF-kB2-like cascade leading to the selective recruitment of RelA/p52 and RelA/RelA dimers on the promoter of several NF-kB target genes including survival and inflammatory genes. These studies also contributed to the identification at a cellular and molecular level of distinct signalling abilities between human and mouse CD28, thus emphasizing the essential need to pay attention to molecular details when transferring results from preclinical models to the bedside. For this long-lasting expertise on CD28, she has been invited by Prof. Choi to write a chapter on CD28 in Encyclopedia of Signaling Molecules, 2nd Edition, Springer.
Our recent studies clarify the pivotal role of membrane phospholipids, in particular phosphatidylinositol 4,5-biphosphate and phosphatidylinositol 3,4,5-triphosphate, and the kinases responsible for their generation (PIP5K, PIP4K and class 1A PI3K) in the regulation of cytoskeleton rearrangement necessary for organizing a complete signaling compartment regulating downstream signaling functions.
More recently, we focused on the role of CD28 in the regulation of the metabolic and inflammatory processes in Multiple Sclerosis (MS), highlighting an important contribution of class 1A PI3K associated with CD28 in the reprogramming of the metabolic processes that maintain/amplify the inflammatory phenotype of peripheral T lymphocytes, thus suggesting class 1A PI3K as a valid therapeutic target for MS. For these contribution in the field of T cell biology, in 2022, I was invited as co-editor of a Research Topic for Frontiers in Immunology entitled “Insights into T cell Biology-2021”, together with Prof. Chen Dong (Tsinghua University, Beijing, China) and Remy Bosselut (NIH, Rockville, United States).
Actually, we are working on two research projects: 1. The characterization of the intracellular signalling events elicited by CD28 in response to bacterial superantigens and its control by CD28 dimer interface mimetic peptides; 2. The ovarian cancer immunotherapeutic efficacy of bispecific antibodies targeting CD28 and MUC1.

POSITIONS AND HONORS
1994-1996 Fellowship for the research on AIDS, by "Istituto Superiore di Sanità", Molecular Immunology Unit (Director: Dr. O. Acuto), Institut Pasteur, Paris France
1996-1997 Fellowship by "Foundation pour la Recherche Medical" Molecular Immunology Unit (Director: Dr. O. Acuto), Institut Pasteur, Paris France
1997-1999 Fellowship by Istituto Pasteur- Fondazione Cenci Bolognetti, Dept. Cell. Biol. and Develop., Sapienza University of Rome
1999-2004 Research contract, Dept. Cell. Biol. and Develop., La Sapienza University of Rome
2004-2012 Assistant Professor, Faculty of SMFN, Sapienza University of Rome
2012-present Associate Professor of Immunology, Sapienza University of Rome

AWARDS:
2000 Principal Investigator of the "Progetto Giovani ricercatori" (CNR, Italy)
2000 Principal Investigator of the "Progetto Giovani ricercatori" (MIUR, Italy)
2004 Principal Investigator of PRIN 2004, (MIUR Italy)
2006 Principal Investigator of PRIN 2006, (MIUR Italy)
2005-2007 Principal Investigator Regional AIRC Grants for Research on “Ovarian Carcinoma”
2012-2013 Principal Investigator FISM Project 2011 (Multiple Sclerosis Italian Foundation)
2008-2017 Principal Investigator of Projects funded by Istituto Pasteur-Fondazione Cenci Bolognetti
2004-at present Principal Investigator of Projects funded Sapienza University of Rome
2017-2019 Principal Investigator FISM Project 2016 (Multiple Sclerosis Italian Foundation)
2020 Principal Investigator together with Raymond Kaempfer (The Hebrew University of Jerusalem) of Vigevani Research Project Prize 2020
201-2022 Principal Investigator FISM Project 2020 (Multiple Sclerosis Italian Foundation)
2023-2025 Coordinator PRIN 2022 PNRR Project (MIUR, 2022)
2024-2026 Principal Investigator PRIN 2022 (MIUR, 2022)

EDITORIAL BOARDS/JOURNAL REVIEW:
- Associate Editor Frontiers in Immunology
- Associate Editor of Cells, MDPI Journals.
- F1000 faculty member

AD HOC REVIEW: Nature Review in Immunology - Journal of Immunology - British Journal of Immunology - BMC Immunology -Molecular Cancer Therapeutics European Journal of Immunology - Apoptosis – Immunology Letters - Cell Death and Differentiation - Cancer Letters - Cell Death and Disease - Journal of Leukocyte Biology – British Journal of Cancer – Cancers – Cells – Embo Journal – Faseb Journal – Molecular Cancer Therapeutics – Oncotarget – Nature Communications – PNAS – Scientific Reports

Scientific reviewer for National and International Projects:
MIUR (FIRB, 2013); ANFR (French National Research Agency, 2013); National Science Center (Cracovia, Polonia, 2016); EEA Grants – Collaborative Research Projects (Romania, 2018); POR FSE 2014/2020, Friuli Venezia Giulia, 2019

INTERNATIONAL COLLABORATION:
Prof. Margot Thome-Miazza, Università di Losanna (Svizzera)
Prof. Robert T. Abraham, The Burnham Institute for Medical Research, La Jolla, California, (USA)
Prof. Christopher E. Rudd, Università di Cambridge, (UK)
Prof. Burkhart Schraven, Università “Otto-von-Guericke”, Magdeburg (Germania)
Prof. Oreste Acuto, Università di Oxford (UK)
Prof. Balbino Alarcon, Università Autonoma di Madrid, (Spagna)
Prof. Kazuyasu Sagakuchi, Università di Okkaido, (Giappone)
Jenny L Persson, Experimental Cancer Research, CRC, Jan Walndenströms gata 35, 205 02, Malmö, Sweden
Jacques A. Nunes, Centre de Recherche en Cancerologie de Marseille - French Biomedical Research Agency (INSERM) U1068, Marseille Cedex 09 - FRANCE
Raymond Keampfer, Hebrew University, Jerusalem