Progetti

Elenco progetti

“ER-Golgi Cycling of Redox Chaperones Control Cancer Adaptive Reactions to Hypoxia Via KDELR”
“ER-Golgi Cycling of Redox Chaperones Control Cancer Adaptive Reactions to Hypoxia Via KDELR”
  • Abstract: Several research lines converge towards the unravelling of a new mechanism of adaptation/ response to hypoxia in tumours. Low oxygen levels are common in malignant tumours and drive enhanced resistance to treatments and poor prognosis. Research in our and other laboratories indicates that a specific mechanism exists that integrates oxidative folding, cyclic transport between ER and Golgi, and intracellular signalling processes to generate an adaptive control system acting as a sensor of hypoxia and as initiator of survival and escape responses in tumour and normal cells. This project aims to dissect this adaptive mechanism starting from the following working model: ER chaperones and enzymes of the redox folding machinery (e.g. ERP44, ERP46, and the enzymes PRDX4 and ERO1- in brief, collectively, redox chaperones) form transient complexes that bind through their C-terminal KDEL motif, or variants thereof, to the KDELR, a protein that cycles between the ER and the Golgi. The KDELR, upon binding these chaperones, drives both their retrograde trafficking to the ER and several G protein-based signalling pathways. This signalling elicits multiple cellular responses including cytoskeleton reorganization, matrix degradation, cell motility/ invasion and proliferation, energy consumption. In tumours, hypoxia enhances the levels of KDELRs and of the redox chaperones, resulting in enhanced matrix degradation and proliferation, helping the survival/ escape of tumour cells (Figure 1). We plan to use advanced imaging, omics and computational techniques to analyse A) the main elements of this model under both control and hypoxic conditions including the dynamics of ER- and Golgi-based molecular system that integrates the functions of redox folding (ERO1, PRDX4, ERP44, ERP46) trafficking (KDELRs) and signalling (G proteins) components and B) the mechanisms by which this system helps the tumour to sense and react to hypoxia. The project has an important application potential in three main areas: one is the field of cancer treatment. A deep understanding of the KDELR / redox cycle and of its functional consequences can create new opportunities for the discovery of treatments targeting hypoxic tumour cells. The second concerns the basic knowledge of how cells coordinate the activity of different molecular modules to optimize their performances under varying conditions. The third is technological. RU2 (IEOS-CNR) is member of the pan European imaging infrastructure Eurobioimaging. The project will stimulate the development of new imaging technologies such as FRET and super resolution imaging applied to KDELR signalling as well as computational analyses of imaging and omics data. In conclusion, the proposed research, by dissecting the KDELR / redox cycle and the related signalling pathways underlying the tumour reactions to hypoxia, and by developing innovative technologies, has the potential to contribute to cancer research and treatment.
  • PI: Prof. Michele Sallese
  • Tipo di progetto: PRIN 2022
  • Finanziatore: MUR
“Study of the pathological mechanisms in the Marinesco-Sjogren syndrome by means of a multi-omics approach”
“Study of the pathological mechanisms in the Marinesco-Sjogren syndrome by means of a multi-omics approach”
  • Abstract: Marinesco-Sjogren's syndrome (MSS) is a rare (<1/1 000 000), currently incurable, autosomal recessive disorder of childhood (OMIM: 248800) characterized by myopathy and cerebellar ataxia. Most of MSS patients carry SIL1 mutations causing an accumulation of unfolded proteins in the ER, the activation of unfolded protein response (UPR) and cell degeneration. The full pathogenic mechanism leading to cell death is unknown, as is which gene/protein should be targeted to treat the disease.   
    Our aims are to identify the molecular pathways triggered by the loss of SIL1 and study their role in cell death/survival. These objectives will be obtained by applying a state-of-the-art multi-omics approach on dried blood spots (DBS). Data mining will be done on clustered multi-omics data using pathway analysis methods. Altered pathways will be confirmed on multiple cells and tissues, while their role in cell death and survival will be studied by RNAi and overexpression. 
  • PI: Prof. Michele Sallese
  • Tipo di progetto: Boost for Interdisciplinarity
  • Finanziatore: MUR-Fondo Promozione e Sviluppo - DM 737/2021. NextGenerationEU

 

Mechanisms of neurodegeneration and phenotypic heterogeneity in inherited prion diseases: physiopathological involvement of prion proteins in membrane trafficking and signaling
Mechanisms of neurodegeneration and phenotypic heterogeneity in inherited prion diseases: physiopathological involvement of prion proteins in membrane trafficking and signaling
  • Abstract: The aims of this project are to investigate the cellular and molecular mechanisms of neurological dysfunction and phenotypic heterogeneity of inherited prion diseases, which are neurodegenerative disorders caused by mutations in the prion protein (PrP) gene. A striking feature of these diseases is their clinical and neuropathological variability. PrP mutations have been associated with different phenotypes: Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). A typical example of how PrP gene variants affect the phenotype is the D178N mutation, which depending on the amino acid encoded at polymorphic site 129, segregates either with CJD (D178N/V129), recognized by dementia and motor abnormalities, or with FFI (D178N/M129), primarily characterized by sleep disruption and autonomic failure. It is thought that different mutations encode misfolded/aggregated PrP variants selectively toxic to specific neuronal populations. Yet, the mechanism by which PrP misfolding/aggregation leads to neuronal dysfunction is unknown. We have studied the metabolism and cellular localization of PrP in primary neurons from transgenic mice carrying mouse PrP homologues of a 72-amino acid insertion associated with a form of GSS, or the D178N/V129 and D178N/M129 mutations. We have found phenotypic differences in these cells, with different mutants accumulating in different compartments of the secretory pathways and producing specific abnormalities of secretory organelles. On the basis of these observations, we will test the hypothesis that intracellular PrP misfolding/aggregation may affect the secretory transport of proteins important for normal neuronal function, and that the phenotypic heterogeneity may be due to different mutants affecting specific membrane trafficking in steps, including the exiting of cargoes from the endoplasmic reticulum, the transport from the Golgi to the plasma membrane, or the endosomal cycling. We will use biochemical and morphological approaches to investigate the efficiency of secretory transport in transgenic mice and cells, as well as in brain autopsies of human patients. Studies will be aimed at understanding whether mutant PrP expression alters the bulk secretory trafficking, or selectively affects a limited number of cargoes, and if the defect is due to a direct effect of mutant PrP on secretory transport or an indirect signaling-mediated mechanism. These studies are expected to define cell-type specific mechanisms of neuronal dysfunction in inherited prion diseases, indicating new modalities of neurotoxicity and potential therapeutic strategies.
  • PI: Prof. Michele Sallese Responsabile di Unità operativa locale
  • Tipo di progetto: Ricerca Finalizzata 2010-2013
  • Finanziatore: Ministero della Salute
COld atmospheric plasma therapy to target head and neck Tumours by A multImodaL approach
COld atmospheric plasma therapy to target head and neck Tumours by A multImodaL approach
  • Acronimo: COCKTAIL 
  • Abstract: Despite impressive scientific, and technological progress, the fight against cancer is still a challenge. COCKTAIL aims at designing a novel target therapy for head and neck squamous cell carcinoma (HNSCC), whose survival is one of the lowest among all major human cancers and has not improved in last decades. To achieve this goal, we will take advantage of the cocktail of reactive species generated by cold atmospheric plasma (CAP) in the liquid media alone and in combination with an anticancer drug, which we will use in a data driven approach:
  • i) to investigate the selective effects of CAP activated media (PAM) against HNSCC
  • ii) to clarify the still unknown mechanisms involved in their therapeutic action
  • iii) to meet the urgent need to standardize protocols and procedures
  • The methodological approach will involve an interdisciplinary team, dealing with chemistry, computational modelling, molecular biology, oral pathology to open a great window of opportunities in the newborn area of Plasma Medicine.

  • PI: Prof.ssa Vittoria Perrotti
  • Tipo di progetto:  Boost for Interdisciplinarity “DM 737/2021 intervento f” D.R. 2182/2021, prot.106637 del 23.12.2021
  • Finanziatore: Unione europea – NextGenerationEU
Bi-functioNal plasma-treated solutions as a new thErapeutiC Tool for cAnceR
Bi-functioNal plasma-treated solutions as a new thErapeutiC Tool for cAnceR
  • Acronimo: NECTAR
  • Abstract: The worldwide incidence of head and neck cancer (HNC) exceeds half a million cases annually, and up to half of the patients with HNC present with advanced disease. Surgical resection remains the mainstay of treatment for many HNCs, although radiotherapy, chemotherapy, targeted therapy, and immunotherapy might contribute to an individual patient’s treatment plan. Irrespective of which modality is chosen, the disease prognosis remains suboptimal, especially for higher-staging tumors. Direct cold atmospheric plasma (CAP) treatments have recently demonstrated a substantial anti-tumor effect in clinical studies. Despite its innovative character, the direct CAP approach cannot be applied to those cases where tumors are hard to reach, or their size would necessitate long treatment times. In order to extend the unique advantages of CAPs, the present project (NECTAR) proposes to study indirect CAP treatment of liquids - named Plasma Treated Water Solutions (PTWS) - enriched with biomolecules that have an ambitious bifunctional effect: efficacy against cancer cells and pathogenic bacteria without altering normal functionalities of healthy cells. The research proposed in NECTAR is at the crossroads of different disciplines and involves researchers working in the fields of chemistry, biology, physics, and medicine. The location of all the actors of the present proposal in the southern part of Italy allows fast exchange of samples and information through a tight interconnection of the centers of research involved. Finally, the innovative character of the proposed research can be translated into meaningful impacts in people's lives by actions that stretch well beyond those traditionally associated with knowledge creation:

    1. generate protocols and tools to standardize the production and analysis of PTWS and implement open science practices;

    2. possibly deposit a patent concerning PTWS with formulations that are suitable to treat different typologies of cells being their effect cell-dependent toward personalized medicine;

    3. set-up a new method to monitor HNC evolution after PTWS treatment through a minimally invasive procedure based on Raman and FTIR analyses;

    4. analyze some distinctive characters of patients affected by HNC through a deep genomic analysis of their microbiome’s

  • PI: Prof.ssa Vittoria Perrotti
  • Tipo di progetto: PRIN PNNR
  • Finanziatore: Unione europea – NextGenerationEU; Ministero dell’Università e della Ricerca

 

Therapeutical effects of Cold atmospheric plasma in Head And Neck Cancer and oral hEalth preservation
Therapeutical effects of Cold atmospheric plasma in Head And Neck Cancer and oral hEalth preservation
  • Acronimo: C.H.A.N.C.E.
  • Abstract:  Head and Neck cancer (HNC) is the sixth most common type of cancer worldwide with an approximate 5-year survival rate of 50%; this is due to a poor response to standard anti-cancer treatments such as chemotherapy and radiotherapy (RT). Surgery combined with adjuvant radiation therapy and/or chemotherapy is the standard of care, but in the case of squamous cell carcinomas (SCCs), patients often experience notable complications related to disease treatments, while showing high rates of recurrence due to radiation treatment resistance. Moreover, patients undergoing radiation treatment will experience changes of the normal physiology of oral soft and hard tissues, leading to mucositis, periodontal disease, dental caries, and overall alteration of the teeth structure (loss of enamel prism structure, degeneration of odontoblast processes, obliteration of dentinal tubules, and gap formation at the enamel-dentine junction), which further compromises nutrition, speech, and social relations. The potential application of alternative and/or adjuvant therapies (i.e. cold plasma, CAP) for HNC-treatment is highly warranted to reduce the impact of traditional RT on oral health and improve the patients’ survival rate and quality of life. Plasma is defined as the fourth state of matter and it is partially or completely ionized gas that reacts with the environment creating a mixture of active components: electrons, ions, radicals, and energetic photons, all of which can in turn interact with the target. Due to advances in physics and biotechnology, nowadays plasma can be easily generated and used at room temperature, reaching high electron temperatures, but very low gas temperatures associated with weak ionization rates. Recently, CAP has been investigated in several medical applications, such as blood coagulation, wound disinfection and healing, tissue and germicidal irradiation and sterilization, skin rejuvenation, tooth bleaching, material surface modifications and crosslinking, and to selectively eradicate cancer cells, while with lower or irrelevant consequences on normal cells. Despite the promising effects of CAP as anti-cancer cell agent, very little is still known on its application in the HNC therapy field and its effects on cellular responses and oral cavity-related effects. Accordingly, this project is aims at a comprehensive evaluation of CAP biological, biochemical and ultramorphological effects on HNC and normal cell lines and tooth tissues. Specifically, CAP will be applied either as stand-alone therapy or in combination to RT (application of CAP before, as well as after RT will both be evaluated). The effects of these treatment modalities will be compared to the effects of RT alone, as well as no treatment (control), aiming to standardize a protocol to reduce adverse effects of RT and improve HNC susceptibility to treatment, but also to investigate the possibility of the individualization of CAP anti-cancer therapy. 
  • PI: co-Pi e responsabilità Unità di Ricerca UniCh: Prof.ssa Vittoria Perrotti
  • Tipo di progetto: PRIN
  • Finanziatore: Unione europea – NextGenerationEU; Ministero dell’Università e della Ricerc
MEchanics vs Cell competition: Hyperelasticity and Adaptation in Vascular Evolutionary Repair and Smart Endoprostheses
MEchanics vs Cell competition: Hyperelasticity and Adaptation in Vascular Evolutionary Repair and Smart Endoprostheses
  • Acronimo: MECHAVERSE
  • Abstract:  Blood vessels are efficient living architectures built by growth and remodeling processes obeying cascades of chemo-mechanical feedbacks that determine a fine balance between tissue turnover and mechanical stress to ensure integrity. Alterations in homeostasis can lead in fact to structural and cellular impairments potentially kindling vascular diseases. In such cases, the direct competition among damage evolution, vessel load-bearing abilities and the remodeling and healing dynamics of multicellular units can mark the boundary between healthy states, stable unruptured morphologies or abrupt strokes. The chance to support vessel functions by restoring favorable conditions can be crucial and, motivated by the social impact of cardiovascular diseases, mechanics can provide valuable tools to predict pathology progression, tissue-prostheses interactions and response to therapies.

    With this in mind, the MECHAVERSE Project aims to develop coupled models of vascular adaptation, where the evolutionary

    interactions -involving cell species, extracellular environment and molecules- are able to meld information from systems biology and cell mechanotransduction with macroscopic growth and remodeling, by determining the influence of in situ stresses on cell functions, also through ad hoc experiments. In this way, multiple scenarios of vessel development could be observed, anomalies in mechanotransduction potentially leading to either cell pathogeneses, such as mutations or metabolic dysfunctions, or stress-based events like abnormal tissue damaging that causes malremodeling activities.

    All these aspects require a consistent multiscale description of tissue response. Pillars of this Project will be advancing theoretical and experimental aspects in vascular hyperelasticity and investigating new approaches for characterizing the multi-physics homogenized vessel behavior, by including possible nonlocal and stochastic effects produced by fiber distributions, to then study situations in which pre-stress, systemic loads, hierarchical microstructural parameters and micro-damage phenomena are in coupling with interspecific remodeling, so paving new strategies for virtual patient-specific trials.

    By exploiting the complementary expertise and the synergy of the involved Units, the mission of the MECHAVERSE Project is to build up advanced theoretical and computational platforms to put in explicit competition cell-mediated interspecific dynamics and stress-dependent processes in deciding fate of vascular remodeling, shedding light on how molecular and mechanical feedbacks across the scales bridge cells interplay with vessel (ultra-)elastic phenomena towards scenarios directly related to clinical manifestation, so contributing to better understanding of diseases and to the development of more effective health technologies for precise medicine, in line with the objectives defined in cluster Health of National Recovery and Resilience Plan.

  • PI: Guya Diletta Marconi (co-PI e PI di Unità locale Uda)-sostituita da Marialucia Gallorini dal 10.02.24 fino al rientro della Dott.ssa Marconi dal congedo per maternità
  • Tipo di progetto: PRIN: PROGETTI DI RICERCA DI RILEVANTE INTERESSE NAZIONALE – Bando 2022 PNRR
  • Finanziatore: Ministero dell'Università e della Ricerca/PNRR
Unity is strength: a novel tool based on human MonoAmine Oxidase B Inhibitors and MEsenchymal Stem Cells Secretome. Novel insights on molecUlar mechaNIsms Of ParkiNson’s disease
Unity is strength: a novel tool based on human MonoAmine Oxidase B Inhibitors and MEsenchymal Stem Cells Secretome. Novel insights on molecUlar mechaNIsms Of ParkiNson’s disease
  • Acronimo: MAOBI-MESCS-UNION
  • Abstract:  The project here reported is aimed at developing a novel tool for the study and treatment of Parkinson’s disease (PD), a motor disorder associated with degeneration of dopaminergic neurons in the substantia nigra pars compacta. The currently available therapeutics are focused on symptoms relief. In this regard human monoamine oxidase B inhibitors (hMAO-Bi) play an important role on one hand, reducing dopamine breakdown, on the other, diminishing oxidative stress due to hydrogen peroxide (H2O2), the by-product of hMAOs enzymatic activity. So, a part of the project is focused on the development of five libraries of new potent and selective hMAO-B inhibitors based on different scaffolds. These compounds will be also evaluated for their antioxidant, radical-scavenging and metal-chelating activities, these properties being all implicated in neuroprotection. Along with “classical” treatments, mesenchymal stem cell (MSCs)-based therapies have emerged as a possible strategy to treat several pathological conditions including neurodegenerative ones. Being able to be artificially directed to differentiate into several specialized cell types, including those of nervous tissues, MSCs can affect two important issues, i.e. illness progression and restoration of tissues functions. So, the project is also focused on the obtainment of human periodontal ligament stem cells (hPDLSCs) that has gaining interests for, among other properties, their easy accessibility being obtained by minimally invasive surgery. These cells, converted to DOP producing ones (hPDLSCs DOP), will be used to generate 2D/3D culture systems from healthy and PD patients as more efficient “bioreactors” to produce therapeutic soluble factors. Indeed, it is now widely accepted that the paracrine signaling through exosomes/extracellular vesicles (EVs) is the main mechanism through which MSCs provide their therapeutic effects, including neuroprotective and neuro-regenerative ones. However, the precise agents produced by stem cells and responsible for their positive activity remain largely unknown. Proteomic and transcriptomic analyses along with the in vitro studies will be performed to assess the molecules and factors enclosed in EVs and involved in their beneficial effects. The study of signal transduction pathway related to PI3K/AKT/mTOR and TLR4/NF-kB on the untreated 2D/3D cell systems or treated with developed compounds and reference hMAO-B inhibitor L-deprenyl, will be also accomplished providing evidence on the molecular machinery involved in the PD evolution and in the cell behavior, after drug treatment. Finally, the administration of selected EVs gained from cells coming from healthy subjects as well as PD patients (un)treated with developed compounds will give first information about the neuroprotective and neuro-regenerative effects evaluated on in vitro model on SH-SY5Y cell line.
  • PI: Francesca Diomede Co-PI (unità locale), Unità di ricerca composta da: Maurizio Piattelli, Simone Carradori
  • Tipo di progetto: PRIN (bando PRIN 2022)
  • Finanziatore: MUR
Implementation of a patient-derived 3D model of glioblastoma multiforme for the developing of extracellular vesicles-based drug delivery system
Implementation of a patient-derived 3D model of glioblastoma multiforme for the developing of extracellular vesicles-based drug delivery system
  • Acronimo: EXANDROID
  • Abstract:  Glioblastoma (GBM) is a common aggressive form of brain cancer characterized by poor prognosis. Despite surgical resection and other available therapeutic treatments, patients often suffer from tumor relapse and succumb due to its rapid growth, chemoresistance, and high invasiveness. GBM tumors are highly heterogeneous, being composed of cellular and matrix components, which contribute to tumor cell invasion, cancer stem cell maintenance, and drug resistance. Novel anticancer strategies are constantly needed to overcome the drawbacks associated with GBM biology. This project aims to enhance the knowledge of GBM biology and heterogeneity, generating and validating a patient-derived 3D model of GBM, that will be studied for its genotypic and phenotypic features. It will develop a personalized drug delivery system, useful for precision medicine applications, based on patient plasma-derived EVs that will be engineered to specifically carry selected antitumor microRNAs (miRNAs), that will be shuttled to target oncogenes associated with this cancer. The GBM 3D model will be studied for the response to the therapeutic tool developed. To establish the GBM 3D model, cells will be obtained from surgical resection and cultured in coculture with astrocytes and microvascular endothelial cells in 3D conditions, using a platform that provides a more physiologically relevant environment for the generation of uniform, size-controlled 3D cultures with organ-like microarchitecture and morphology. This model will enable us to overstep the disadvantages of the use of animal models and allow a better understanding of the disease. Furthermore, it will be assayed for new targeted therapies based on engineered GBM-derived EVs, isolated from patients. The use of cutting-edge technologies, such as the implementation of a novel 3D tissue-like model in vitro that recapitulates the heterogeneous microenvironment of GBM; the use of proteomics approach and miRNAs profiling; the employment of patient-derived EVs loaded with specific molecules, will ensure the achievement of the objectives foreseen in each work package. The multidisciplinary approach and the joint efforts of the Research Units with complementary expertise represent a truly unique opportunity in the field of brain cancer research in Italy, which will allow for significant improvements in GBM patient management.
  • PI: Francesca Diomede Co-PI (unità locale) , Unità di ricerca composta da: Paola Lanuti
  • Tipo di progetto: PRIN (bando PRIN 2022 PNRR)
  • Finanziatore: MUR
Novel Biomaterial-based Device for the Treatment of Progressive MS - An Integrated Pan- European Approach
Novel Biomaterial-based Device for the Treatment of Progressive MS - An Integrated Pan- European Approach
  • Acronimo: PMSMatTrain
  • Abstract:  Principal Investigator di Unità operativa MARIE SKLODOWSKA-CURIE ACTIONS Innovative Training Networks (ITN) Call: H2020-MSCA-ITN-2018 (813263). Project Title: Novel Biomaterial-based Device for the Treatment of Progressive MS - An Integrated Pan- European Approach
  • PI: prof.ssa Damiana Pieragostino, Il coordinatore è Dr Una FitzGerald, University of Galway-Ireland
  • Tipo di progetto: MARIE SKLODOWSKA-CURIE ACTIONS Innovative Training Networks (ITN) Call: H2020-MSCA-ITN-2018 (813263)
  • Finanziatore: Horizon europe
Exploring the therapeutic potential of perinatal cell SECRETomes
Exploring the therapeutic potential of perinatal cell SECRETomes
  • Acronimo: SECRET
  • Abstract:  Principal Investigator di Unità operativa MARIE SKLODOWSKA-CURIE ACTIONS Innovative Training Networks (ITN) Call: HORIZON-MSCA-2023-DN-01 (101168752). Project Title: Exploring the therapeutic potential of perinatal cell SECRETomes
  • PI: di unità locale prof.ssa Damiana PieragostinoIl coordinatore è Ornella Parolini, Università Sacro Cuore-Roma
  • Tipo di progetto: MARIE SKLODOWSKA-CURIE ACTIONS Innovative Training Networks (ITN) Call: HORIZON-MSCA-2023-DN-01 (101168752)
  • Finanziatore: Horizon Europe
Role of IFITM2 in SARS-CoV-2 infection : a potential new target for therapy
Role of IFITM2 in SARS-CoV-2 infection : a potential new target for therapy
  • Acronimo: 
  • Abstract:  
  • PI: Coordinatore Prof.ssa Damiana Pieragostino
  • Tipo di progetto: PRIN 2022
  • Finanziatore: Fondo per il Programma Nazionale Ricerca PNR