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In a longstanding collaboration with Francesco Moccia (currently at the Università degli Studi del Molise, Campobasso) we explore different aspects of intracellular Ca2+ signaling. Initiated in the Lab of Luigia Santella from dissecting the roles of NAADP and IP3 in fertilization of starfish oocytes, the collaboration proceeded during my postdoc in the Lab of Armando Genazzani with characterization of functional interaction between ER and lysosomal Ca2+ stores. In collaboration with Egidio D'Angelo (UniPV) we discovered a role for astroglial calcineurin in neuronal excitability. We contributed with our expertise in subcellular Ca2+ probes and in biochemistry of Ca2+ signaling toolkit to dissect pathophysiological aspects of Ca2+ signaling in different celular models such as endothelial progenitors; endothelial colony-forming cells from tumoral environment and grown on a light-sensitive polymer (with Maria Rosa Antognazza and Francesco Lodola); brain endothelium; metastatic colorectal cancer cells; human megacaryocytes (with Alessandra Balduini, UniPV); brain endothelium and astrocytes (with Giulio Sancini, UniMiB); and tumor-infiltrating lymphocytes (with Daniela Montagna, UniPV). Recently, with Anrea Gerbino (UniBA), Alessandra Fiorio Pla (UniTO), and Francesco Lodola (IIT) in a report of a symposium organized in frame of the 72nd Annual Meeting of the Italian Society of Physiology, we discussed emerging topics of Ca2+ signaling.
In a longstanding collaboration with Alexej Verkhratsky from the Manchester University we explore role of neuroglia in physiological and pathological contexts. Mainly focusing on the role of astrocytes in Alzheimer's disease (2014; 2016; 2024), we exploit expertise of our colleagues to delve deeper into such aspects of pathophysiology of neuroglia as astrocytic Ca2+ signaling with Alexey Semyanov, ER stress and UPR with Marco Corazzari, and the role of astrocytes, microglia and oligodendrocytes in AD, PD and HD with Carlos Matute and Fabio Cavaliere.
In frame of a project financed by Cariplo Foundation, we reported that genetic astrocyte-specific deletion of calcineurin regulatory subunit CNB1 prevents AD-related neuropathology, neuroinflammation and preserves cognitive performance in 3xTg-AD mice.
Currently, in collaboration with Gianluigi Forloni and Claudia Balducci (Mario Negri Institute, Milan) and with participation of Valentina Saverio (UPO), and whith a financial support from PNRR programan and Italian Ministry of Health, we are working on understanding the molecular mechanisms of this positive effect of deleting CNB1 from astrocytes.
Recently, we reported that the physical distance between ER and mitochondria at mitochondria-ER contact sites (MERCSs) represents a critical parameter for Ca2+ control of mitochondrial bioenergetics.
These seminal finding generated an array of collaborative projects including:
Initial observation about impairment of mitochondrial Ca2+ uptake in AD astrocytes led us to focus on MERCS. Using a well characterized model of partially immortalized hippocampal astrocytes from 3xTg-AD mice, we showed that MERCS alterations are central to AD-related protein dyshomeostasis. Furthermore, in collaboration with Anna Maria Eleuteri and Laura Bonfili (UNICAM), stabilizing MERCSs at a defined distance of 20 nm we were able to correct mitochondrial Ca2+ signaling and previously reported protein degradation impairment in AD astrocytes.
In collaboration with Alexej Verkhratsky (UniManchester), Tito Cali and Marisa Brini (UniPD). We analyzed the dysfunction of ER-mitochondrial Ca2+ transfer in neurodegenerative diseases (here) and discussed a possible role for MERCS dysfunction and Ca2+ alterations in AD-related protein dyshomeostasis (here and here).
Recently we contributed to the development of a novel Ca2+ sensor for MERCS (with Tito Cali (UniPD), Yusuke Nasu and Robert Campbell (UniTokyo)). Using this sensor we demonstreated that the physical ER-mitochondrial distance is critical for the IP3R-mediated ER Ca2+ release.
A PhD project of Justyna Malecka, in collaboration with Riccardo Miggiano, Marcello Manfredi (UPO) and other colleagues. We use mass spectrometry proteomics of whole lysates and fractionated MERCS to follow how cellular proteome changes upon MERCSs manipulation. We showed that even a tiny difference in MERCS distance leads to profound remodeling of cellular protein and lipid homeostasis; and discussed in vitro and in vivo effects of artificial MERCS tethering.
PhD project of Elisa Tonelli, in collaboration with Cristina Meregalli (UniMIB), Silvia Giatti (UniMI) and Carla Distasi (UPO). This is a NextGenEU-PNRR-funded collaborative project aimed at identification of new mechanisms of chemioterapy-induced peripheral neuropathy (CIPN) and molecular targets for neurosteroids as anti-CIPN therapy.
Financed by the Cariplo Foundation to Giulia Dematteis (Cariplo giovani), in collaboration with Giovanni Marsicano (INSERM, Bordeaux).
PNRR-financed, a cascade-call project led by Mariagrazia Grilli (UPO) with participation of Dmitry Lim and Laura tapella.
Led by Laura Tapella in collaboration with Marcello Manfredi (UPO) and Silvia Pozzi (UnivLaval, Quebec).
An Italian Ministry of Health funded, multicenter project Pharma-HUB, aims at establishing a national platform for drug repurposing in reare paediatric diseases, with focus on ataxia-telangiectasia (A-T). Consortium led by Emauela Esposito (UniME). UPO Unit is presented by PI Mariagrazia Grilli with participation of Luigia Grazia Fresu, Carla Distasi, Emilio Marengo, Elisa Robotti and Dmitry Lim. From our Lab in this project were involved as postdocs Giulia Dematteis, Marianna Moro and Paola Zanetta. The main Task of UPO Unit is generation and characterization of novel cellular models of A-T for drug screening and repurposing. Recently, we reported that urine-derived stem cells (USC) with CRISPR/Cas9-mediated deletion of ATM gene present alterations characteristic for A-T and can be differentiated in functional myocytes with an A-T-relevant Ca2+ signaling and contractile dysfunction.
A collaboration with Eleonora Aronica (UniAmsterdam and AMC) and talented PhD students Alessia Romagniolo (AMC), Rozemarijn Kalf (AMC) and Giulia Dematteis (UPO) aimes at investigating Ca2+ signaling and mitochondrial dysfunction in glial cells in tuberous sclerosis complex protein (TSC)-associated epilepsy. A recent report dissects Ca2+-related dysregulation in human astrocytes prepared from resected epileptic foci of patients with mutations of tuberous sclerosis complex protein (TSC). We found that in TSC astrocytes both Ca2+ signaling and mitochondrial functions are severely impaired and this correlated with single-nuc transcriptomic profile of TSC tissues and proteome of TSC astrocytes.
Plasmids and other material, generated in our lab, are available either from Addgene, or upon direct request to Dmitry.Lim@uniupo.it.