Biology and Pharmacology of Aging, Inflammatory Disorders, Cancer and Neurodegeneration

Macroarea: Pharmacology

ERC Sectors: LS – Life Sciences ERC subfields: LS7_4 Pharmacology and pharmacogenomics (including drug discovery and design, drug delivery and therapy, toxicology); LS4_4 Fundamental mechanisms underlying ageing; LS4_6 Fundamental mechanisms underlying cancer; LS5_1 Neural cell function, communication and signalling, neurotransmission in neuronal and/or glial cells; LS5_7 Neurological disorders (e.g. neurodegenerative diseases, seizures); LS6_4 Immunological mechanisms in disease (e.g. autoimmunity, allergy, transplantation immunology, tumour immunology)

Lab Managers: Marco Racchi (Full Professor), Cristina Lanni (Associate Professor), Cristina Travelli (Associate Professor), Erica Buoso (Assistant Professor)

Junior Staff: Davide Voltan (PhD Student)

Scientific Consultant: Stefano Govoni (Prof. Emeritus)

1. Glymphatic system as new player in the gut-brain axis

This research aims to investigate the relationship between gut dysbiosis and glymphatic system (GS) alterations, involved in several pathologies across the gastrointestinal, the immune and nervous system. This research will define the generation of glymphatic alterations in a mouse model of dysbiosis, and the development of neurological disorders. Information about the onset of dysbiosis will be parallelly obtained in a model of glymphatic damage (the sleep deprivation). Sleep disorders impair the GS and may promote neurological disorders due to the ineffective elimination of potentially neurotoxic waste products. Increasing evidence supports a relationship between sleep disorders and dysbiosis. Nevertheless, a direct relationship between dysbiosis and GS alteration has not yet been explore.

2. The role of Pin1 from cancer to neurodegeneration: what are the implications of its derangement in Alzheimer’s Disease

Pin1 acts as key context-dependent tuner of multiple signaling pathways with a central role in directing cells toward survival or death. In pathological contexts, an imbalance in Pin1 activity and/or expression may exacerbate diseases by hijacking cellular processes regulated by Pin1 to sustain pathological mechanisms. Investigations on Pin1-catalyzed conformational regulation and its biological and pathological significance should help to elucidate the molecular events triggering neurodegeneration in AD. Since the possibility to selectively target Pin1 in AD is unexplored, this research line gives the opportunity to explore the possibility to target Pin1 alterations in pathological tissues. Such unbiased expansion of the rationale and the targets may help to achieve major advances in the field of AD research.

3. Study of the cytokine eNAMPT in inflammatory disorders and cancers

Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the NAD salvage-pathway in mammals that catalyzes the synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (NAM) and 5-phosphoribosylpyrophosphate (PRPP). NAMPT has also been shown to be a secreted protein, known as extracellular NAMPT (eNAMPT), a pro-inflammatory cytokine that seems to acts on TLR4 controlling inflammation. The levels of eNAMPT are increased in inflammatory disorders and in several type of tumors. The Lab works with a murine monoclonal antibody against eNAMPT (C269) and a humanized antibody (collaboration with Prof. Garcia, Aqualung therapeutics) that neutralize eNAMPT and that are a novel pharmacological tool that can be used to unravel the therapeutic potential of targeting eNAMPT. Currently, the lab is focusing on 3 main projects: I. Study the role of eNAMPT in controlling triple negative breast cancer progression II. Study the role of the cytokine eNAMPT in the pathogenesis and progression of Inflammatory bowel diseases (IBD) III. Study the involvement of eNAMPT in autoimmune gastritis and celiac disease

4. Study of RACK1 and its-associated pathway in aging and cancer

Receptor for Activated C Kinase 1 (RACK1) is a key mediator of various pathways involved in central cellular activities such as cell proliferation, transcription, translation and neuronal functions. Alterations in RACK1 homeostasis are associated with brain disorders and breast cancer.

I. OXER1 and RACK1-associated pathway: a promising therapeutic target in breast cancer. This study aims to identify a new pathway to be used for the design of innovative and rational therapeutic strategies in the context of the personalized treatment of breast cancer.

II. RACK1 as a neurobiological link in brain disorders. RACK1 covers an important role in translation and can associate to stress granules (SGs) that along with RNA metabolism are significantly emerging as novel potential targets for the comprehension of the molecular events leading to neuronal deficits

5. Immune response and Endocrine Disrupting Chemicals (EDCs): RACK1 as a bridge between the endocrine and the immune systems

RACK1 plays a crucial role in the immune context, since a tight correlation has been demonstrated between its expression and immune cells activation. A hormone-related regulatory element for glucocorticoids and androgens in RACK1 promoter highlights that hormone-active substances can affect the immune response via RACK1 modulation. EDCs are substances in the environment, food sources, personal care products and manufactured products interfering with the endocrine system. EDCs have been linked with immune alterations due to inflammation-enhancing and immunosuppressive properties and a role for EDCs in the increased incidence of cancers, autoimmune diseases, and allergies in most industrialized countries has been hypothesized. Elucidating mechanisms behind EDCs plausible immunological implications will lead to advances in the field of public health safety.

• Fagiani F, Di Marino D, Romagnoli A, Travelli C, Voltan D, Di Cesare Mannelli L, Racchi M, Govoni S, Lanni C. Molecular regulations of circadian rhythm and implications for physiology and diseases. Signal Transduction and Targeted Therapy, 2022. https://doi.org/10.1038/s41392-022-00899-y
• Fagiani F, Vlachou M, Di Marino D, Canobbio I, Romagnoli A, Racchi M, Govoni S, Lanni C. Pin1 as Molecular Switch in Vascular Endothelium: Notes on Its Putative Role in Age-Associated Vascular Diseases. Cells. 2021 Nov 24;10(12):3287. https://doi.org/10.3390/cells10123287
• Fagiani F, Govoni S, Racchi M, Lanni C. The Peptidyl-prolyl Isomerase Pin1 in Neuronal Signaling: from Neurodevelopment to Neurodegeneration. Mol Neurobiol. 2021 Mar;58(3):1062-1073. https://doi.org/10.1007/s12035-020-02179-8
• Colombo G, Clemente N, Zito A, Bracci C, Colombo FS, Sangaletti S, Jachetti E, Ribaldone DG, Caviglia GP, Pastorelli L, De Andrea M, Naviglio S, Lucafò M, Stocco G, Grolla AA, Campolo M, Casili G, Cuzzocrea S, Esposito E, Malavasi F, Genazzani AA, Porta C, Travelli C*. Neutralization of extracellular NAMPT (nicotinamide phosphoribosyltransferase) ameliorates experimental murine colitis. J Mol Med (Berl). 2020;98:595-612. https://doi.org/10.1007/s00109-020-01892-0
• Travelli C, Consonni FM, Sangaletti S, Storto M, Morlacchi S, Grolla AA, Galli U, Tron GC, Portararo P, Rimassa L, Pressiani T, Mazzone M, Trovato R, Ugel S, Bronte V, Tripodo C, Colombo MP, Genazzani AA, Sica A. Nicotinamide Phosphoribosyltransferase Acts as a Metabolic Gate for Mobilization of Myeloid-Derived Suppressor Cells. Cancer Res. 2019. https://doi.org/10.1158/0008-5472.CAN-18-1544
• Galli U, Colombo G, Travelli C, Tron GC, Genazzani AA, Grolla AA. Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy. Front Pharmacol. 2020;11:656. https://doi.org/10.3389/fphar.2020.00656
• Buoso E, Kenda M, Masi M, Linciano P, Galbiati V, Racchi M, Dolenc MS, Corsini E. Effects of Bisphenols on RACK1 Expression and Their Immunological Implications in THP-1 Cells. Front Pharmacol. 2021 Sep 21;12:743991.  https://doi.org/10.3389/fphar.2021.743991
• Brivio P*, Buoso E*, Masi M, Gallo MT, Gruca P, Lason M, Litwa E, Papp M, Fumagalli F, Racchi M, Corsini E, Calabrese F. The coupling of RACK1 with the beta isoform of the glucocorticoid receptor promotes resilience to chronic stress exposure. Neurobiol Stress. 2021 Jul 26;15:100372. https://doi.org/10.1016/j.ynstr.2021.100372. *co-first authors
• Masi M, Garattini E, Bolis M, Di Marino D, Maraccani L, Morelli E, Grolla AA, Fagiani F, Corsini E, Travelli C, Govoni S, Racchi M, Buoso E. OXER1 and RACK1-associated pathway: a promising drug target for breast cancer progression. Oncogenesis. 2020 Dec 11;9(12):105. https://doi.org/10.1038/s41389-020-00291-x

National collaborations

• Ghelardini Carla e Lorenzo Di Cesare Mannelli, Università di Firenze
• Rosini Michela, Università di Bologna
• Di Marino Daniele, Università Politecnica delle Marche
• Pittaluga Anna, Università di Genova
• Trabace Luigia, Università di Foggia
• Caraci Filippo, Università di Catania
• Beatrice Arosio, Università di Milano
• Sabina Sangaletti, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
• Ambra A Grolla and Giorgia Colombo, Università del Piemonte Orientale, Novara
• Davide Ribaldone, Ospedale le Molinette, Torino
• Luca Pastorelli, Università degli Studi, Milano
• Marco Lenti e Antonio di Sabatino, Ospedale San Matteo, Pavia
• Irene Paterniti, Università degli Studi di Messina
• Adele Romano, Università La Sapienza di Roma
• Elisabetta Panza, Università degli Studi di Napoli Federico II
• Cristina Scavone, Università degli Studi della Campania Luigi Vanvitelli
• Enrico Garattini, Istituto di Ricerche Farmacologiche Mario Negri, Milano
• Simona Collina e Pasquale Linciano, Università degli studi di Pavia
• Laura Calabrese e Paola Brivio, Università degli Studi di Milano
• Emanuela Corsini, Università degli Studi di Milano

International collaborations

• Tamas Fulop, University of Sherbrooke, Canada
• Joe G. N. "Skip" Garcia, MD, University of Arizona College of Medicine
• Tucson (US) and CEO of Aqualung Therapeutics
• Bolis Marco, IOR Institute of Oncology Research (CH), Università della Svizzera Italiana(USI), Swiss Institute of Bioinformatics (SIB)
• Benjamin Wolozin, Boston University, School of Medicine, MA, US
• Marija Sollner Dolenc, University of Ljubljana, Slovenia

• PRIN202039WMFP: “New interventional approaches on multiple inflammatory pathways involved in regeneration after trauma and aging-associated diseases”
• PRIN 2020SCBBN2: “Glymphatic system: a new player in the gut-brain axis. Natural resources to maintain homeostasis”
• PRIN 2020SEMP22 “Regulation of autophagy by N-acylethanolamines as a promising approach for the treatment of inflammatory-based diseases: from neurodegeneration to metabolic disorders”
• 2019: Ricerca Biomedica Fondazione Cariplo: Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT): role in the pathogenesis and progression of Inflammatory Bowel Diseases
• PRIN2017B9NCSX: “Study of the crosstalk between multiple pathways in the regulation of inflammatory processes in models of chronic and degenerative diseases”

Microscopia confocale a fluorescenza, Centro Grandi Strumenti, Pavia

Imaging a Risonanza Magnetica e Micro Tomografia a raggi X, Centro Grandi Strumenti, Pavia