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Invited researcher Sergey Anatolyevich Lukyanov
Contract number
11.G34.31.0017
Time span of the project
2010-2014
Head of the laboratory

As of 30.01.2020

23
Number of staff members
180
scientific publications
4
Objects of intellectual property
General information

Name of the project: Fluorescent proteins: new approaches to researching mechanisms of physiological and pathological processes in living systems

Strategy for Scientific and Technological Development Priority Level: в


Goals and objectives

Research directions:

- Developing technologies of in vivo observation of tumor cell using fluorescence bioimaging and genetically encoded markers and sensors

- Research of capabilities of genetically encoded photosensibilizers for directed destruction of tumor cells

- Developing modern approaches to researching mechanisms of action of anti-tumor medications and early response of tumors to treatments based on optical and molecular technologies

Project objective: Creating conceptually new fluorescent tools for diagnostics and therapy of cancer. for molecular biology research


The practical value of the study

  • We have shown possibility of using red fluorescent proteins (RFP) for studying processes in organisms.
  • Our Laboratory has developed a technology to observe cells and cellular structure using RFP.
  • We have obtained mammal cell lines carrying the gene of one of those proteins (KillerRed) that can be used as a photosensibilizer to destroy tumor cells.
  • We have shown phototoxic and immunogenic qualities of KillerRed in experiments involving animals.
  • We have created fluorescent sensors for detecting intracellular hydrogen peroxide (HyPer, HyPer-2) and measuring intracellular рН (SypHer-2, SypHer-Red). Methods have been developed to visualize hydrogen peroxide and pH in living cells and tissues.
  • We have created genetically encodable sensors of activity of caspases and phases of cellular cycle based on red fluorescent proteins.
  • The Laboratory has developed methods of analysis of energy metabolism of living cells and tissue based on registering fluorescence of endogenic metabolic co-factors NADP and FAD.
  • We have developed approaches to analysis of microviscosity of tumors using fluorescent molecular rotors and fluorescence-lifetime imaging microscopy.
  • Our researchers have proposed original methods for producing temporary cell cultures from samples of tumors of patients and testing individual chemical sensitivity.
  • We have demonstrated possibility of multiparameter assessment of response of tumor cells to chemotherapy.

Education and career development:

  • 7 employees of foreign companies have completed training at the Laboratory. Employees represented companies such as Andor Technology Ltd. (UK), JenLab (Germany), Carl Zeiss (Germany), Perkin Elmer (USA).
  • We have organized 4 international internships for employees of the Laboratory at international science and education centers: The European Molecular Biology Laboratory (Germany), Institute of Photonic Technologies, Jena, (Germany), Lund University (Sweden), National University of Ireland (Ireland).
  • We have organized 8 international internships for employees of the Laboratory at Russian scientific organizations: Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Evrogen Ltd, ANALIT Production, Saint Petersburg University of Information Technologies, Mechanics and Optics – ITMO, Institute of Developmental Biology of the Russian Academy of Sciences, Lobachevskiy Nizhniy Novgorod State University.
  • We have compiled 5 special courses for students of 5th-6th years, intern, and resident physicians in bioengineering, optical bioimaging, fluorescent proteins in medicine, modern technologies of fluorescent in microscopy for problems of biomedicine and technologies of fluorescent bioimaging for biomedicine.
  • 8 term papers have been completed on the topics studied by the Laboratory.
  • 1 doctoral dissertations, 6 candidate dissertations, 4 bachelor dissertations.
  • We have created the School for Young Scientists in Fundamental Medicine (2016) supported by the Research Institute of Biomedical Technologies of the Nizhniy Novgorod State Medical Academy. Lessons are held every two weeks, lecture are delivered by employees of the Laboratory and invited researchers, students of the school participate in scientific work of the Laboratory, deliver keynotes at youth conferences.

Organizational and structural changes:

  • We have created an innovative laboratory that conducts fundamental and applied research that correspond to world-class level. The laboratory studies molecular basics of pathogenesis of oncological conditions as well as developing concepts of applying achieved results (creating modern methods of diagnostics and targeted treatment) in experimental and clinical medicine.
  • The Laboratory has organized a new scientific under supervision of the leading scientist (S. A. Lukyanova). On the basis of the Privolzhsky Research Medical University (ex Nizhniy Novgorod State Medical Academy) a new Research Institute for Biomedical Technologies has been created that currently has 30 employees.

Other results:

  • Every year employees of the Laboratory participate in international and all-Russian conferences delivering invited keynotes (SPIE Photonics West, SPIE Photonics Europe, International Conference on Laser Applications in Life Sciences, Topical problems of biophotonics, FLIM workshops, Advanced Imaging Methods Workshop, CTERP International conference Translational Research in Cell Therapy, Russian Oncology Congress, National Regenerative Congress) and in scientific events for young scientists, postgraduates and undergraduates as invited lecturers (ADFLIM school, Methods of Histological Research and Imaging). Over the period between 2010 and 2018 employees of the Laboratory have delivered 45 invited keynotes.
  • The Laboratory has organized and conducted: international conferences «Nanobiophotonics» (2011, 2013, 2015) и «Biophotonics in Cancer Research» (2017) within the «Topical problems of biophotonics» symposium; international scientific seminars «Biophotonics in Stem Cell Research» (2017), «Tumor and Stem Cells Biology», «Biophotonics (2015) and Developmental Biology» (2013) within the «Topical problems of biophotonics» symposium; the «Nanotechnologies in living systems» (2010-2014) and «Biomedical technologies» (2015-2018) sections within the Scientific session of young scientists and students of the Privolzhsky Research Medical University; research and practice conference «Life Science Imaging» (1-2 April 2014); international seminar «Multiphoton tomography: possibilities and research» (22 May 2014).
  • We have published monographs:

1. Zagaynova E.V., Druzhkova I.N., Mishina N.M., Ignatova N.I., Dudenkova V.V., Shirmanova M.V. Imaging of Intracellular pH in Tumor Spheroids Using Genetically Encoded Sensor SypHer2. In: Dmitriev R. (ed.) Multi-Parametric Live Cell Microscopy of 3D Tissue Models. Advances in Experimental Medicine and Biology 1035. Springer, Cham (2017).

2. Shirmanova M.V., Shimolina L.E., Lukina M.M., Zagaynova E.V., Kuimova M.K. Live Cell Imaging of Viscosity in 3D Tumour Cell Models. In: Dmitriev R. (ed.) Multi-Parametric Live Cell Microscopy of 3D Tissue Models. Advances in Experimental Medicine and Biology 1035. Springer, Cham (2017).

3. Shirmanova M.V., Sergeeva T.F., Druzhkova I.N., Meleshina A.V., Lukina M.M., Dudenkova V.V., Shcheslavskiy V.I., Becker W., Belousov V.V., Mishina N.M., Zagaynova E.V. Metabolic Shifts and Intracellular pH in Cell Proliferation and Differentiation (Chapter 10). In: K. König (ed.) Multiphoton Microscopy and Fluorescence Lifetime Imaging. Applications in Biology and Medicine. De Gruyter Open, 2018. 421 p.

  • The following patents have been registered:

1. Patent of the Russian Federation No. 2458129 granted on 10 August 2012. Priority granted on 25 April 2011. Isolated nucleic acid, encoding the KillerRed proteins (variations), isolated protein (variations), expression cassette, cell containing expression cassette. Authors: K. A. Lukyanov, E. O. Serebrovskaya, S. A. Lukyanov.

2. Patent of the Russian Federation No. 2493260 granted on 20 September 2013. Priority granted on 30 November 2011. Isolated nucleic acid, encoding a fluorescent biosensor for detecting hydrogen peroxide, expression cassette, cell producing biosensor, isolated fluorescent biosensor, isolated nuclei acid encoding fluorescent biosensor operatively fused with nucleic acid encoding a signal of intracellular localization. Authors: D. S. Bilan, V. V. Belousov, S. A. Lukyanov.

3. Patent of the Russian Federation No. 2491342 granted on 27 August 2013. Priority granted on 25 April 2011. Isolated nucleic acid encoding operatively fused intramolecular dimer of the KillerRed protein, expression cassettes, acid producing chimera protein and containing expression cassette, isolated chimera protein. Authors: K. A. Lukyanov, E. O. Serebrovskaya, S. A. Lukyanov.

4. Patent of the Russian Federation No. 2497121 granted on 27 October 2013. Priority granted on 10 October 2012. A method to assess concentration of hydrogen peroxide in tumor cells under impact of anti-tumor drugs. Authors: A. S. Belova, V. V. Belousov, A. A. Brilkina, E. V. Zagaompva, A. V. Maslennikova, N. M. Mishina, S. A. Lukyanov, A. Orlova, E. A. Sergeeva, N. M. Shakhova.

5. Patent of the Russian Federation No. 2493260 granted on 10 June 2013. Priority granted on 30 November 2011. Isolated nucleic acid encoding fluorescent biosensor, expression cassette, cell producing fluorescent biosensor. Author: D. S. Bilan, V. V. Belousov, S. A. Lukyanov.

6. Patent of the Russian Federation No. 2519936 granted on 20 June 2014. Priority granted on 13 September 2012. A method of photodynamic tumor therapy. Author: M. V. Shirmanov, E. V. Zagainova, S. A. Lukyanov, E. O. Serebrovskaya, L. B. Snopova, M. V. Bugrova, E. A. Minakova, M. A. Sirotkina, V. A. Kamenskiy.

Collaborations:

  • Imperial College London (UL): joint research in visualizing microviscosity, joint publications in the Scientific Reports journal, a chapter in a book by the Springer publishing house
  • JenLab (Germany): mutual consultations on using multiphoton fluorescence tomography, joint research involving multiphoton fluorescence tomography
  • Becker & Hickl GmbH (Germany): joint research in fluorescence-lifetime imaging, joint scientific events (international symposium Topical Problems of Biophotonics, FLIM seminars), joint publications in journals Scientific Reports, Optics Letters, a chapter in a book of the De Gruyter publishing house
  • University College Cork (Ireland): joint research of oxygen status of tumors, developing chemical oxygen sensors based on nanostructures
  • Gunma University (Japan): joint research of oxygen status of tumors, developing chemical oxygen sensors based on iridium, a joint publication in the Optics Letters journal 
  • University of Pennsylvania (USA): joint research of oxygen state of tumors, scientific seminars and experience exchange, mutual consulting in phosphorescent imaging of oxygen
  • University of Virginia (USA): joint research to study metabolism of tumor ells, joint scientific events (international symposium Topical Problems of Biophotonics), scientific seminar to exchange experience in metabolic imaging, mutual consulting
  • Institute of Applied Physics of the Russian Academy of Sciences (Russia): joint scientific events, international symposium Topical Problems of Biophotonics
  • Institute of Metal-Organic Chemistry of the Russian Academy of Sciences (Russia): joint research in developing new photosensibilizers for photodynamic therapy of tumors, joint publications in journals: «Biochimica et Biophysica Acta – General Subjects», «General chemistry journal», «Biophysis»
  • Institute of Chemical Physics of the Russian Academy of Sciences (Russia): joint research in developing new photosensibilizers for photodynnamic therapy of tumors, joint publications in journals -  «Journal of Analytical and Bioanalytical Techniques», «Journal of Photochemistry» and Photobiology
  • Institute of Bioorganic Chemistry of the Russian Academy of Sciences (Russia): joint research of oncological processes using new genetically encoded sensors, joint publications in journals: «Biochimica et Biophysica Acta – General Subjects», «Scientific Reports, Biochimica et Biophysica Acta – Molecular Cell Research», a chapter in a book published by the Springer publishing house
  • Privolzhskiy Regional Medical Center (Russia): joint research in individualizing chemotherapy in patients with colorectal cancer; joint research on applying multiphoton and fluorescence-lifetime microscopy for analysis of liver under induced cholestasis, a joint publication submitted to the «Clinical Colorectal Cancer» journal; publications in «Proceedings of SPIE»
  • First Moscow State Medical University (Russia): joint research in regenerative medicine and tissue engineering, joint publications in journals Cell Adhesion and Migration, Biofabrication, Nanomedicine
  • Saint Petersburg State University (Russia): joint research to deloping new oxygen sensors, joint publications in the «RSC Advances» journal
  • «Evrogen» CJSC (Russia): joint research in geneti engineering and cellular biology, developing materials for research
  • N.N. Blokhin Russian Oncology Center (Russia): joint research in experimental oncology using mice tumors, scientific seminars and experience exchange, mutual consulting in synthesis, sustaining and utilizing of tumor models
  • P. A. Gertsen Moscow Research Institute for Oncology (Russia): joint research in experimental oncology using mice tumor models, scientific seminars and experience exchange, mutual consulting in producing and utilizing tumor models
  • Lobachevskiy Nizhniy Novgorod State University (Russia): student exchanges, providing scientific base for completing candidate and masters dissertations
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Shirmanova M.V., Yuzhakova D.V., Snopova L.B., Perelman G.S., Serebrovskaya E., Lukyanov K.A., Turchin I.V., Subochev P., Lukyanov S.A., Kamensky V.A., Zagaynova E.V.
Towards PDT with Genetically Encoded Photosensitizer KillerRed: A Comparison of Continuous and Pulsed Laser Regimens in an Animal Tumor Model. PLoS ONE 10(12): e0144617 (2015).
Shirmanova M.V., Druzhkova I.N., Lukina M.M., Matlashov M.E., Belousov V.V., Snopova L.B., Prodanetz N.N., Dudenkova V.V., Lukyanov S.A., Zagaynova E.V.
Intracellular pH Imaging in Cancer Cells in vitro and Tumors in vivo using the New Genetically Encoded Sensor SypHer 2. Biochimica et Biophysica Acta – General Subjects 1850(9): 1905–1911 (2015).
Shirmanova M.V., Druzhkova I.N., Lukina M.M., Dudenkova V.V., Ignatova N.I., Snopova L.B., Shcheslavskiy V.I., Belousov V.V., Zagaynova E.V.
Chemotherapy with Cisplatin: Insights into Intracellular pH and Metabolic Landscape of Cancer Cells in vitro and in vivo. Scientific Reports 7(1): 8911 (2017).
Sergeeva T.F., Shirmanova M.V., Zlobovskaya O.A., Gavrina A.I., Dudenkova V.V., Lukina M.M., Lukyanov K.A., Zagaynova E.V.
Relationship between Intracellular pH, Metabolic Co-Factors and Caspase-3 Activation in Cancer Cells during Apoptosis. Biochimica et Biophysica Acta – Molecular Cell Research 1864(3): 604–611 (2017).
Druzhkova I.N., Shirmanova M.V., Lukina M.M., Dudenkova V.V., Mishina N.M., Zagaynova E.V.
The Metabolic Interaction of Cancer Cells and Fibroblasts – Coupling between NAD(P)H and FAD, Intracellular pH and Hydrogen Peroxide. Cell Cycle 15(9): 1257–1266 (2016).
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