Several diseases, including inflammatory disorders such as arthritis and genetic pathologies such as Paget’s disease, are characterized by an abnormal osteoclast function, which causes uncontrolled bone resorption. Furthermore, osteolytic lesions characterize the establishment of tumor metastases to the skeleton that typically indicate a short-term prognosis in cancer patients. Studies over the last decade have revealed that dysregulated lipid metabolism is one of the fundamental metabolic alterations that enable the establishment of these pathological conditions. In the last years, I investigated the role of lipolytic enzymes in the osteoclastogenesis process, highlighting the involvement of a secretory phospholipase (sPLA2-IIA) in the regulation of osteoclast differentiation and function using different experimental models, both in vitro and in vivo. In addition, the role of PLA2 metabolites was deepened, through the signaling of lysophospholipid receptors, turning GPR55 into a promising candidate to develop novel therapies for the treatment of bone-related pathologies. As G-protein-coupled receptors (GPCRs) are ‘druggable’ targets in treatment and prevention of a vast majority of pathologies, we have developed novel strategies for the targeting of two pro-inflammatory GPCRs, GPR55 and the complement receptor C5aR1, with allosteric regulators, both peptides and small molecules, identifying useful tools for innovative therapeutic approaches.
These lines of investigation were carried on thanks to the synergistic collaborations with Italian and foreign colleagues, and the financial support from the industries.
– Mangini M, Iaccino E, Mosca MG, Mimmi S, D’Angelo R, Quinto I, Scala G, Mariggiò S (2017) Peptide-guided targeting of GPR55 for anti-cancer therapy. Oncotarget. 8(3):5179-5195. doi: 10.18632/oncotarget.14121.
– D’Angelo R, Mangini M, Fonderico J, Fulle S, Mayo E, Aramini A, Mariggiò S (2019) Inhibition of osteoclast activity by complement regulation with DF3016A, a novel small-molecular-weight C5aR inhibitor. Biomed Pharmacother. 123:109764. doi: 10.1016/j.biopha.2019.109764.
– Mosca MG, Mangini M, Cioffi S, Barba P, Mariggiò S (2021) Peptide targeting of lysophosphatidylinositol-sensing GPR55 for osteoclastogenesis tuning. Cell Commun Signal. 2021 Apr 26;19(1):48. doi: 10.1186/s12964-021-00727-w.
– Mangini M, D’Angelo R, Vinciguerra C, Payré C, Lambeau G, Balestrieri B, Charles JF, Mariggiò S (2022) Multimodal regulation of the osteoclastogenesis process by secreted group IIA Phospholipase A2. Front Cell Dev Biol. 2022 Aug 29;10:966950. doi: 10.3389/fcell.2022.966950.
- 2023 – 2025 Head of a Research Unit within the “Fondo ordinario per gli enti e le istituzioni di ricerca” (FOE) – Invecchiamento (MIUR) in the Department of Biomedical Sciences (DBS) – CNR. (26 k€).
- 2023 – 2025 Head of a Research Unit within the PRIN 2022 PNRR (MIUR) – Prot. P2022CWSTY – Glycerophospholipid signaling at the interface between osteoclast and T cells. (117 k€).
- 2023 – 2024 Direction and coordination of research activities within “Contratto di Ricerca Preclinica per Enti o Istituti di Ricerca” signed between Dompé farmaceutici S.p.A. and IBBC-CNR. (27 k€).
- 2018 – 2019 Head of a Research Unit within Progetto di ricerca & Sviluppo. PO FESR 2014‐2020 – Regione Campania: Sviluppo di Approcci Terapeutici INnovativi per patologie neoplastiche resistenti ai trattamenti (SATIN) “Preclinical evaluation of small synthetic molecules and creation of a platform for the preclinical study of new anti-neoplastic therapies”. (37.5 k€).
- 2012 – 2022 Scientific and technical management of research activities within 5 different “Contratti di Ricerca Preclinica per Enti o Istituti di Ricerca” signed between Dompé farmaceutici S.p.A. and IBP/IBBC-CNR. 2020-2022 “C5a/C5aR1 role in human models of osteoclastogenesis” (54 k€); 2019 “Establishment of a human model of osteoclastogenesis” (27 k€); 2018 “Modulation of osteoclast differentiation by C5aR antagonists (RAW264.7 cell model) (26 k€); 2016-2017 “Cellular model optimisation to monitor the activity of allosteric modulators on C5aR coupling with G-proteins” (52 k€); 2012-2015 “GPCRs quali bersagli molecolari nello sviluppo di nuovi farmaci per malattie rare”. (30 k€).
- 2013 – 2017 Head of a Research Unit within the PRIN 2012CK5RPF (MIUR), “Development and preclinical validation of a nano-technological platform that targets the minimal residual disease (MRD) in Cancer”. (117 k€).
Trainee
Garzillo Giordana