Radiobiologie – Project ELI-09

Project ELI-09

Advanced biological methods for investigating stress responses of normal and pre-leukemic cells under irradiation at ELI-NP – applications for astrobiology and FLASH radiotherapy / CELLI

PROGRAM

PNCDI 3, Program 5 – Research in strategic domains, Sub-program 5.1 The research, development and innovation program for technologies in the field of ultra-power lasers – ELI-RO. Project type: R&D.

Place of the project in the framework/context of the ELI-NP White Book

LGE/III.5 Biological systems under irradiation

TDR4 topic 2.6. Biological systems under irradiation

Project duration

01.10.2020 – 30.09.2023

Consortium

Coordinator

”Victor Babeș” National Institute of Pathology, Bucharest, ROMANIA (IVB)

Project directorDr. Gina MANDA

Partner 1

“Horia Hulubei” National Institute for R&D in Physics and Nuclear Engineering, Măgurele, ROMANIA (IFIN-HH)

Project responsible: Dr. Andi Sebastian Cucoanes

Budget

1,000,000.00 Lei

Useful links

ELI-RO IFA http://www.ifa-mg.ro/eli/

ELI –NP http://www.eli-np.ro/

“Victor Babeș” National Institute of Pathology https://www.ivb.ro/v3/ro/

“Horia Hulubei” National Institute for R&D in Physics and Nuclear Engineering https://www.nipne.ro/

Project Summary

Background: An important objective of ELI-NP is to demonstrate the biological effects of the laser-generated pulsed multi-energetic ionizing radiations using cells under irradiation (LGE/III.5, TDR4). The proposed radiobiology experiments are designed to bring original contributions in the field of astrobiology and radiotherapy. Astrobiology investigations in the context of ELI-NP were initiated by the coordinator of the present project (IVB) in the previous Eli-RO project (13-ELI/2016) through which a dedicated biomedical platform was built, as well as the prototype of the irradiation cassette for exposing cells in the E5 area at ELI-NP. Moreover, preliminary results were obtained to demonstrate our innovative biomedical strategy for investigating proliferating monocytes under irradiation using available continuous radiations. The study was mainly  financed by ELI-RO and had the logistic support of European Space Agency (ESA) and GSI Center for Heavy Ion Research (Germany) through the AO-2017-IBER program financed by ESA.

Main project objective: to enlarge the portfolio of advanced biological investigations addressing the interaction of cells with radiation, relevant for astrobiology and FLASH radiotherapy studies at ELI-NP.

Scientific objectives:

(1) To implement the concept of “network medicine” at ELI-NP for understanding the mechanisms underlying the response of normal and pre-leukemic cells exposed to pulsed, multi-energetic radiations produced at ELI-NP, as compared to conventional continuous radiations;

(2) To sustain this network approach by advanced biomedical in vitro methods that will be used for preliminary experiments at ELI-NP: metabolomic investigations using hyperpolarized nuclear magnetic resonance; reactive oxygen species measurements using electron paramegnetic resonance; functional and transcriptomic investigations using multi-color flow cytometry and pathway-focused PCR arrays;

(3) Integration of data in biologic networks for highlighting the potentially unique biological effects of the radiations generated at ELI-NP.

Technologic objectives:

(1) Design of experiments regarding the interaction of cells with radiation generated by high-power lasers;

(2) Design and fabrication of cells holders and their integration into the irradiation installations at ELI-NP and IFIN-HH;

(3) Development of the biology laboratory built at ELI-NP;

(4) Setup of a project-dedicated biobank at ELI-NP; (5) First biologic experiments at ELI-NP using electron and proton beams; (6) knowledge and technology transfer to ELI-NP.

Secondary objectives:

(1) Strengthening of the multi-disciplinary consortium built in the 13-ELI project, by increasing its competence and by recruiting young researchers;

(2) Generation of scientific and technical knowledge within the consortium regarding the investigation of cells under irradiation;

(3) Increase of the international visibility of ELI-NP and its partners by publications and communications in highly ranked journals and conferences;

(4) development of international collaborations for submitting large-scale projects.

Multi-disciplinary consortium: ”Victor Babes” National Institute of Pathology (coordinator, IVB) and „Horia Hulubei” National Institute for Physics and Nuclear Engineering (partner, IFIN-HH), which has as its main core a team from ELI-NP. The consortium joins expertise in the fields of physics, biophysics, biology, biochemistry and radiochemistry. Most of the team members have collaborated since 2014 for elaborating TDR4 and thereafter in the frame of the 13-ELI project (ELI-RO).

Expected results:

(1) Customized cells holders for irradiation at Eli-NP;

(2) Tritium-labelled biomolecules (≥3);

(3) panel of biomarkers specific for cellular responses to radiation; (

4) Technology transfer protocol towards ELI-NP, including operational procedures and technical reports;

(5) Biobank at ELI-NP;

(6)  Publications (≥4) and communications (≥8);

 (7) Workshops (2);

(8) Summer school;

(9) Astrobiology project proposal to the AO-IBER program for continuing the collaboration with ESA and GSI;

(10) PhD thesis (synchronisation and coherent

OUTLINE OF THE MAIN TASKS

International collaboration

IVB

Astrobiology

The IVB team is involved in astrobiology through the project “Redox signalling and the transcription factor NRF2 as therapeutic target for counteracting the deleterious effects of spaceflight environment”, 2018-2021. The project is financed by the European Space Agency through the Programme INVESTIGATIONS INTO BIOLOGICAL EFFECTS OF RADIATION USING THE GSI ACCELERATOR FACILITY (AO-2017-IBER). In this project we are specifically collaborating with Dr. Nicole Averbeck and Dr. Ulrich Weber from GSI Helmholtz Center for Heavy Ion Research (Darmstadt, Germany), as well as with the . iEuropean biophysics group established through the above mentioned Programme.

Redox biology

1) Collaboration with the EU-ROS consortium (http://eu-ros.eu/);

2) Collaboration with Prof. Antonio Cuadrado from the Autonomous University of Madrid, Spain in the field of the transcription factor Nrf2 which is critically involved in the activation of the antioxidant response and may be a valuable drug target for modulating oxidative stress in pathological conditions, including exposure to ionizing radiation. Prof. Cuadrado is coordinating the project “Knowledge transfer in redox biology for developing advanced molecular tools in neurodegenerative diseases – focus on the signature of NRF2 transcription factor in diagnosis and therapy”, acronym REDBRAIN, project ID P_37_732, 2016-2021, financed by European Funds for Regional Development through the Competitiveness Operational Program 2014-2020, that is currently implemented in IVB. Moreover, we were partners with Prof. Cuadrado in the M-Era.Net project NANOTHER (2016-2019).

ELI-NP

The Biophysics and Biomedical Applications Laboratory, representing the main ELI-NP structure involved in the project, developed collaborations with a several institutions from Romania and abroad, in various research directions, in the fields of radiobiology, hyperpolarized spectroscopy and NMR methods such as: Molecular imaging of radiation effects, metabolic networks involved in the cellular response to radiation; New biomarkers for radiation effects;  Free-radical generation effects of radiation in water and HDO as a nuclear spin polarisation source for biomarkers; Magnetic resonance methods for biomarker follow-up.

The collaborations include Laboratoire des BioMolécules of École normale supérieure Paris, Institute of Biological Chemistry of Vienna University, and also Romanian institutions such as Research Institute and the Faculty of Chemistry, both of the University of Bucharest, Institute of Organic Chemistry of the Romanian Academy, Amethyst Radiotherapy Clinic, and Carol Davila University of Medicine and Pharmacy. Support programs: the National Core Program, Fundamental Research Program, “Experimental – Demonstrative Project” program. The research program of ELI-NP includes also the study of biological systems under irradiation at E4 and E5 Experimental areas. This direction belongs to the broader field: “Evaluation of cosmic stressors effects in materials, electronic devices and biological systems” and it is described in TDR4. The biophysics related part has been developed in close collaboration with „Victor Babes” National Institute of Pathology, however the collaboration is broader and includes GSI Helmholtz Centre for Heavy Ion Research, National Institute for Laser, Plasma and Radiation Physics Romania, University of Bucharest, West University Timisoara, Romania and Queen’s University Belfast. Support programs: Core Program, Space Technology and Advanced Research Program (STAR).

IFIN-HH

The IFIN-HH/DRMR team develops research activities in the field of ionising radiation dosimetry in cooperation with Laboratoire National Henri Becquerel (LNHB) – CEA Saclay France, University of Bucharest-Faculty of Physics (Absorbed dose simulation, developing of new dosimetry systems; treatability of dosimetry measurements). Support programs: the national Core Program, the IFA CEA Program.

COST proposals in the field of CELLI submitted to the 2020 Call

• Carbon molecular nanostructures in space – Nanospace (OC-2020-1-24955)
• Applied nUclear phySics and bioPhysics at acCElerators – AUSPICE (OC-2020-1-24469)
• Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases –BenBedPhar (OC-2020-1-24760)