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THE PHYSICS DEPARTMENT OF PAVIA UNIVERSITY, ITALY, IS THE COORDINATOR OF NECTAR PROJECT.
THE WORK IS BASED ON AN INTERDISCIPLINARY EU NETWORKS OF RESEARCH TEAMS FROM 7 ACADEMICS AND 1 INNOVATIVE START-UP.
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NECTAR Coordinator and lead beneficiary of WP1 - Management, and WP7 - Dissemination, education and training.
Due to its nuclear physics competences and the presence within the Pavia University Campus of the research nuclear reactor of L.E.N.A. laboratory (Laboratory Applied Nuclear Energy), UNIPV will be the responsible and executor of all the experiments involving neutron irradiations (from protein water solutions up to animals, plus benchmark measurements of innovative detector developed by Raylab, WP4).To be more specific, this means the active participation of UNIPV in the following tasks, either as leader or as participant: 4.2 (n-irr of Aβ aggregates water solutions), 5.1 (cerebral cell cultures n-irr, with or without CENI agents), 5.2 (n-irr of AD animal models and naïve mice), 6.1(n-irr of AD animal models and naïve mice).
To support this experimental activity UNIPV will perform Monte Carlo studies to plan and optimize the neutron irradiation of all the samples involved in NECTAR, which means from protein solutions (task 3.4) up to small animals (task 3.5). Still related to the strong Monte Carlo computational know-how of UNIPV, this partner will be the responsible and executor of all the simulations to calculate the treatment planning of CENI in human brain medical images (task 3.6, in collaboration with UKJ) and in the theoretical modelling studies of CENI irradiation toxicity in cells (task 5.3).
Experience in: Neutron Capture Therapy (NCT), radiobiological model of cell death after high LET IRs irradiation.
Facilities and tools: Laboratory of Applied Nuclear Energy L.E.N.A. (neutron irradiation facilities), MCNP and PHITS Monte Carlo codes, NCT-Plan Treatment Planning System, BIANCA code.
Associate Professor at the Physics Department of Pavia Universitysaverio.firstname.lastname@example.org
Associate Professor at the Physics Department of Pavia Universityfrancesca.email@example.com
PhD in Physics, Associate Professor at the Physics Department of Pavia Universitysilva.firstname.lastname@example.org
PhD in Physics, Associate Professor at the Physics Department of Pavia Universitynicoletta.email@example.com
PhD student at Physics Department of Pavia Universityvaleria.firstname.lastname@example.org
Lead beneficiary of WP2 - Capture-Enhanced Neutron Irradiation (CENI) agents.
Responsible and executor of all the tasks of WP2 thanks to its chemical know-how and experience to guarantee the development of the CENI agents.
Because the involvement and use of the B/Gd agents is crucial for several steps of NECTAR, clearly UNITO is an active partner also in the following tasks: T3.1 (characterization of Aβ aggregates), T4.2 (n-irr + B/Gd of Aβ water solutions), T5.1 (in vitro toxicity of CENI), T5.2 (in vivo toxicity of CENI), T6.1 (in vivo efficacy of CENI). Specifically, UNITO will provide the required amounts of CENI agents to perform the experiments.
As a NECTAR partner, UNITO will be involved in WP1-management and WP7-dissemination.
Finally and very importantly, UNITO will take care of all the related patent filling procedures which will eventually developed from the chemical synthesis phases and agent development.
Experience in: i) the development and preparation of nanosized agents for the delivery of both therapeutic and MRI agents; ii) the development of innovative Boron carriers in the field of Boron Neutron Capture Therapy based on as an example: PLGA nanoparticles, liposomes, Low Density Lipoproteins (LDL), apoferritin; iii) the development and testing of new compounds for Alzheimer Disease treatment; iv) the setup of efficient cellular labeling procedures for both “in vitro” and “in vivo” pre-clinical models.
Facilities and tools: the resources necessary to the implementation of the project are available at the Center for Molecular Imaging (CIM). CIM is located at the Molecular Biotechnology Center (MBC) of the University of Torino where the experimental work will be carried out. At MBC research at pre-clinical level (cellular and animal models) is routinely performed with the aim of its translation to the clinics. CIM is equipped with two MRI scanners operating at 1 and 7T, high resolution NMR instrument working at 600 MHz, one field cycling relaxometer (0.01-10 MHz, Smart Tracer, Stelar), one field cycling relaxometer (0.01-20 MHz, Stelar Spinmaster) equipped with a 40mm 0.5 T FC magnet and a dedicated 11 mm solenoid detection coil. Equipment for the synthesis and purification of organic compounds (HPLC-MS), a laboratory for the preparation and characterization of nanosystems, a dynamic scattering laser instrument for the determination of the dimensions and zeta potential of nanoparticles (Malvern Zetasizer), and an inductively coupled plasma mass spectrometry (ICP-MS, Element 2, Thermo-Finnigan, Rodano (MI), Italy). Cell culture (equipped with normo- and hypoxia incubator), histopathology, optical and confocal microscopes, FACS and animal facilities.
All the work concerning the synthesis of new CENI agents will be carried out at the Department of Chemistry of UNITO well equipped for synthesis and product purification: i.e. 600 MHz NMR spectrometer, four GC, GC-mass spectrometer, FT-IR, analytical and semi-preparative HPLC with diode array detector, ESI mass connected to an analytical HPLC, polarimeter.
Associate Professor at the Chemistry Department of Torino Universityannamaria.email@example.com
Associate Professor at the Molecular Biotechnology and Health Sciences Department of Torino Universitysimonetta.firstname.lastname@example.org
Researcher at the Chemistry Department of Torino Universitypolyssena.email@example.com
Technician at the Molecular Biotechnology and Health Sciences Department of Torino Universitydiego.firstname.lastname@example.org
Post-doc fellow at the Molecular Biotechnology and Health Sciences Department of Torino Universityvaleria.email@example.com
Lead beneficiary of WP6 - Capture-Enhanced Neutron Irradiation (CENI) Effectiveness.
IRFMN is the main partner of NECTAR consortium with the experience and know-how to handle properly and effectively Aβ proteins as well as AD animal models and related healthy counterparts. For this reason, IRFMN is first of all the partner in charge of Aβ procurement, synthesis and preparation for all the experiments, from the level of water solutions up to animals.
In addition, IRFMN is responsible for: (i) APP/PS1 mouse purchasing and maintenance, (ii) APP/PS1 mouse evaluations at behavioral and neuropathological level upon neutron irradiation, (iii) evaluations of residual neurotoxicity of irradiated Aβ aggregates on cell cultures.
To go specifically through the tasks of the project, IRFMN will be the leader partner for the following tasks: T3.1 (Aβ aggregates characterization), T4.2 (Aβ depolymerization by CENI), T4.3 (residual toxicity of Aβ aggregates in vitro and in vivo), T5.2 (in vivo CENI toxicity), T6.1 (in vivo CENI effectiveness); while IRFMN will be a participant in the following steps: T2.4 (Aβ binding assay through SPR).
Due to their general objectives, IRFMN is involved also in the management (T1.1-T1.3) of the project as well as the dissemination, communication and training activities (T7.1-T7.4).
Experience in: IRFMN has a long lasting experience with in-vivo studies, having analyzed and characterized several animal models of AD both at behavioral and neuropathological level. Importantly, several therapeutic approaches were previously tested on AD mice, which implies a large experience with the assessment of therapeutic efficacy at multiple level within the complex, multi-factorial pathological scenario of AD. IRFMN has also a very large experience with peptide synthesis including Aβ, the characterization and analysis of Aβ aggregate formation and the determination of changes within the peptide aggregation process. Furthermore, IRFMN will share its expertise with SPR technique, allowing the assessment of protein binding and affinity.
Facilities and tools: The Mario Negri Institute is fully equipped with all the facilities, know-how and technologies required to execute the experiments described in the project. IRFMN disposes of: stereotaxic and gas anesthesia systems for brain surgery; various behavioral apparatus connected to the Noldus system; three locations with cryostats for brain slice collection. Two Olympus confocal microscopes and one Nikon structured illumination microscope for immunofluorescence imaging. Two light microscopes supported by the analysis program for histological analysis. One virtual stage Nikon microscope for image acquisition. Two work stations with the IMARIS software for imaging post-processing. Imaging systems for quantitative analysis of Western blots. The Institute provides also a very large high-standard Specific Pathogen Free animal facility. For in vitro experiments the department is fully equipped for chemical and solvent storage and handling, cell culture maintenance, several cell-culture laminar flow hoods and incubators. It also includes an advanced equipment for cell sorting (FACS), biochemical analysis (absorption and fluorescence plate readers) and microscopy (optical e confocal microscopes, epifluorescent microscope equipped with thermostatic chambers for time-lapse live imaging).
Researcher at Mario Negri Institute for Pharmacological Research IRCCSclaudia.firstname.lastname@example.org
PhD Student at the Neuroscience Department of Mario Negri Institute for Pharmacological Research IRCCSletizia.email@example.com
Head of the Neuroscience Department at Mario Negri Institute for Pharmacological Research IRCCSgianluigi.firstname.lastname@example.org
Researcher at Mario Negri Institute for Pharmacological Research IRCCSmarco.email@example.com
Researcher at Mario Negri Institute for Pharmacological Research IRCCSedoardo.firstname.lastname@example.org
Lead beneficiary of WP4 - High LET ionizing radiations effects.
Raylab is the partner of NECTAR consortium with the know-how and experience to take care of the studies, design, prototyping and realization of the innovative instruments for neutron spectrometry and micro- and nano-dosimetry, both from the mechanical and engineering point of view as well as under the theoretical perspective. For the latter, Raylab will take advantage of the collaboration with Milano Politecnico, subcontractor of Raylab in NECTAR project. In addition, Raylab will be the main responsible of the measuring campaigns with the named innovative tools at the neutron facilities available at L.E.N.A. laboratory of Pavia University.
Due to the very high potential in patent filling, Raylab will take care of the commercial exploitation of the IP coming from the developed instruments.
List of tasks for which Raylab is leader/participant: T1.1-T1.3; T3.2 (Geant4 and Geant4-DNA modelling of NCT high LET secondaries effects), T3.3 (Geant4 modelling of Aβ irradiation, in particular sharing the measured data taken at T4.1); T4.2 (sharing the measured data taken at T4.1); T5.1 and T5.2 (spectrometric and dosimetric characterization of neutron irradiation fields used in T5.1 for in vitro tests and in T5.2 for in vivo experiments); T6.1 (as T5.2); T7.1-T7.4.
Experience in: design and development of ultra low-power and low-noise electronics for detection systems; neutron dosimetry and spectrometry experts: designer and patent owner of the first active neutron portable spectrometer working in real time; advanced competences in Monte Carlo simulations, micro and nano dosimetry, experimental measurements on complex field of ionizing radiations; mechanical design, software and firmware programming. Raylab is spin-off of Politecnico di Milano.
Facilities and tools: Americium Beryllium neutron irradiation facility (fast neutrons) and the thermal neutrons facility ESTHER at Politecnico di Milano (Italy), subcontractor of RAYLAB. Advanced electronic lab for prototyping, testing and data analysis; professional CAD and PCB designer tool; numerical simulation code workstation.
IRSN is the public expert in France on nuclear and radiation risks. Activities in dosimetry range from experimental and computational absorbed dose characterization to the Monte Carlo modelling of the main physical and biological mechanisms involved in biological consequences of an irradiation. In this context, IRSN is an expert in Geant4-DNA MC code and contributes actively to its develop within the Geant4-DNA international collaboration.
Lead beneficiary of WP3 - Dosimetry and CENI planning.
IRSN has the role of leader of WP3- dosimetry and planning, thanks to its long experience and know-how on dosimetry topics. IRSN will have the responsibility for all the Geant4 and Geant4-DNA simulations of the capture processes with a particular attention to the micro- and nano-meter scale levels (T3.2 and T3.3). The Geant4 Monte Carlo tools and results will be used in task T4.2 to link the observed effects on irradiated proteins to meaningful micro- and nano-dosimetry quantities. In addition, the Geant4 tools developed in T3.2 and T3.3 will be used directly or as a second validation tool in T3.4 (planning of Aβ water solutions irradiation) and T3.5 (planning of small animal irradiation).
List of tasks for which IRSN is leader: T3.2, T3.3, T3.4
List of tasks for which IRSN is participant: T1.1-T1.3; T3.1 (Aβ aggregates characterization); T3.5, T3.6; T4.1 and T4.2 (link between Geant4 models and experimental results); T7.1-T7.4.
Experience in: experimental and computational dosimetry, Monte Carlo modeling and developments, dose-effect correlation.
Facilities and tools: Geant4 and Geant4-DNA codes, DNAFabric software for the generation of molecular geometries, neutron calibration facilities via radionuclide sources (CEZANE facility) or via a particle accelerator providing monoenergetic neutrons fields (AMANDE facility), RX and γ metrological irradiation facilities, beta multi source irradiator 85Kr, 90Sr and 147Pm.
Lead beneficiary of WP5 - CENI safety.
SU has the role of leader of WP5- safety, thanks to its long experience and know-how on low doses and low dose rate effects in humans with focus on radiation protection. SU will study the safety and toxicity of the CENI procedure using in vitro cell cultures (T5.1) and will support UNIPV in the theoretical modelling studies of T5.3 organizing and sharing the data collected from cells. In addition, SU will provide support in all tasks investigating toxic effects, in particular at cellular level, i.e. T4.3 (residual toxicity of n-irradiated Aβ aggregates when administered to neuronal and microglia cultures) and T5.2 (CENI toxicity tests in vivo).
List of tasks for which SU is leader: T5.1
List of tasks for which SU is participant: T1.1-T1.3; T4.3; T5.2 and T5.3; T7.1-T7.4
Experience in: The group has long experience in working with mixed radiation fields of high and low LET radiations as well as low dose rates. Cellular and cytogenetic responses are evaluated throughout the project to study the radioprotection aspects.
Facilities and tools: Radiation facilities are available for exposure of cells to concominant or separate low LET X-rays or gamma radiation and high LET alpha particles at high or low dose rates. Equipment for cell work and for most molecular biology or cytogenetic analysis methods are available within the group or the department.
Researcher at Stockholm University, Department of Molecular Biosciences, The Wenner-Gren Insitutelovisa.email@example.com
Researcher at Stockholm University, Department of Molecular Biosciences, The Wenner-Gren Insitutesergey.firstname.lastname@example.org
Thanks to its clinical perspective, UKESSEN will provide all over the project a critical judgement of the preclinical results obtained in cells and animals for a possible future translational phase and the possible implementation of clinical trials. Thus UKESSEN is not leader of any tasks but involved in the following list of activities to provide an internal advisory feedback, specifically:
- T2.3 and T2.4: these two tasks regards critical aspects of the CENI agents, i.e. BBB crossing and selective Aβ binding; thanks to its experience in pre-clinical as well as clinical AD studies, UKESSEN can give useful suggestions and feedback during the developing phase of the carriers to effectively address the topics of crossing and binding;
- T4.3: this task will focus both on in vitro as well as in vivo experiments; thanks to its experience in AD preclinical studies, UKESSEN can assist IRFMN in the analysis of the collected results, with eventually the possibility of verifing the most crucial or controversial results;
- T5.1 and T5.2: as for the previous task, both in vitro and in vivo experiments are planned and again UKESSEN experience in AD preclinical studies will be offered to IRFMN and SU to analyze the collected results;
- T6.1: being the main goal of the project, to prove the effectiveness of the CENI procedure in AD animal models, and also taking into account the various aspects which could lead to a null result in term of efficacy, UKESSEN experience and know-how will be exploited to help and assist IRFMN in analysing the collected results and to propose tests and evaluations to investigate the most reasonable underling mechanisms compatible with the observed effects
- T7.1-T7.4: the impact of the new technology of NECTAR on the AD community (clearly including also AD M.D.) is huge so the dissemination and communication of the hypothesis and the results since the very beginning of the project are fundamental to fully achieve NECTAR objectives; being a clinical unit, UKESSEN will be directly involved in the design, organization and delivery of such dissemination and communication actions towards the AD medical community.
Finally, being a member of the consortium, UKESSEN will participate in the management of the project (WP1).
Experience in: TBD.
Facilities and tools: TBD.
Professor, Neurologist and Geriatrician at the Department of Geriatrics, University of Duisburg-Essenrichard.email@example.com
Laboratory Manager at Institute Group 1 (IG1), Geriatric Center Haus Berge, University Duisburg-Essenalexander.firstname.lastname@example.org
List of the WPs where UKW is actively partecipating:
- WP3: UKW participates in the last task (3.6, in collaboration with UNIPV) devoted to the calculation of human brain pan-irradiation to evaluate theoretically the clinical scenario of CENI application for a future translational phase of the technology; UKW will participate as clinical expert in the initial definition of parameters to perform the treatment planning and in the evaluation of the 2-3 best final solutions obtained by UNIPV; in addition, UKW will procure and share 1-2 medical brain images (MRI or CT) evaluated as good samples of human brain for the goals of the project together with UNIPV and UKESSEN;
- WP5: in this WP, UKW participates as an advisory with clinical background to evaluate the eventual toxic effects observed in cells and AD animals; specifically, UKW can help in suggesting and identifying strategies to avoid/mitigate the named toxicity starting from the radiotherapy experience on humans;
- WP7: in this WP, UKW can help NECTAR consortium in reaching the radiotherapy medical community to spread and disseminate NECTAR results towards the first possible user of the future new technology of CENI (radiotherapists and medical physicists);
- WP1: as NECTAR partner, UKW will help and assist the Coordinator and the other members of the consortium in managing the project.
Experience in: TBD.
Facilities and tools: TBD.
FET (Future and Emerging Technologies) Open European program provides support for the earliest stage of new cutting-edge researches in any field of science and technologies. It is now evolved in the EIC Pathfinder Open, that continues the mission embracing high-risk, high- gain projects and interdisciplinary collaborations that drive technological breakthroughs. The program aims to go beyond existing knowledge and encourages visionary thinking to pave the way for innovations, radical new ideas and novel technologies, with potential to create new markets and opportunities.
This project has received funding from the European Union's Horizon 2020 research and innovation programme under Grant Agreement No. 964934
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