Institute of Molecular Biology. Institute of Molecular Biology named after V. A. Engelhardt of the Russian Academy of Sciences Institute of Molecular Biology of the Russian Academy of Sciences

Institute of Molecular Biology named after. V.A. Engelhardt of the Russian Academy of Sciences (IMB RAS) established on April 26, 1957 as the Institute of Radiation and Physico-Chemical Biology of the USSR Academy of Sciences. On June 18, 1965, by resolution of the Presidium of the USSR Academy of Sciences, the Institute was renamed into the Institute of Molecular Biology of the USSR Academy of Sciences. On March 22, 1988, the Institute was named after V.A. Engelhardt. Currently, the Institute is part of the Department of Biological Sciences of the Russian Academy of Sciences and is a non-profit scientific organization engaged in fundamental research in the field of molecular biology.

The founder and first director of the Institute for 27 years was an outstanding biochemist and molecular biologist, academician of the USSR Academy of Sciences and the USSR Academy of Medical Sciences - Vladimir Aleksandrovich Engelhardt (1894-1984). In 1984-2003 The institute was headed by academician Andrei Darevich Mirzabekov (1937-2003). In 2004, Corresponding Member of the Russian Academy of Sciences Alexander Aleksandrovich Makarov was elected director of the Institute.

When organizing the Institute, the active support of V.A. Engelhardt received assistance from outstanding Russian scientists: P.L. Kapitsa, I.V. Kurchatov, A.N. Nesmeyanov, I.L. Knunyants, I.E. There M. Among those who, together with V.A. Engelhardt stood at the origins of the Institute, were A.A. Baev, A.E. Braunstein, Ya.M. Varshavsky, B.P. Gottikh, M.N. Meisel, A.A. Prokofieva-Belgovskaya, V.I. Tovarnitsky, L.A. Tumerman, I.A. Utkin, I.A. Klochkov.

The basic principle laid down by V.A. Engelhardt when organizing the Institute is harmonious combination and the development of biological, biochemical, chemical, physical and mathematical approaches in molecular biological research.

In 2004, the Institute updated its structure. A number of scientific departments were abolished or reorganized, a new laboratory of transcription factors, a group of molecular bases of cell therapy and a group of chromosomal bases of evolution were organized.

As of January 1, 2009, the Institute had 28 scientific divisions: 23 laboratories and 5 groups. The total number of employees of the Institute is 298 people, including 191 researchers. Among them are one academician of the Russian Academy of Sciences and four corresponding members of the Russian Academy of Sciences, two members of the European Academy, 40 doctors of science and 121 candidates of science.

IMB is the initiator of research on the structural and functional analysis of human and plant chromosomes, tRNA and aminoacyl-tRNA synthetases, protein crystallography, molecular enzymology, reverse transcription, decoding of nucleotide sequences of DNA and RNA, molecular immunology, nucleosome structure, mobile genetic elements of animals, DNA -ligand interactions, biological microchips, genomic fingerprinting.

From 1988 to 2002 IMB, as the lead institute, headed genomic research in the USSR and Russia within the framework of the federal program “Human Genome” (headed by A.A. Baev and L.L. Kiselev).

Currently, scientific research is carried out in the following main areas:

Molecular and Cellular Engineering; bioengineering;

Oncogenomics, oncodiagnostics, oncoprognostics, oncovirology;

Mobile and repeating genetic elements of animals and their evolution;

Molecular Immunology;

Structure and molecular dynamics of biopolymers;

Creation of new biologically active compounds;

Genetic enzymology;

Signal transmission at the molecular and cellular levels;

Genomic and proteomic bioinformatics;

Development of fundamental principles of new molecular and cellular technologies, bionanotechnology;

Plant genomics.

IMB RAS ranks 15th among all research institutes and universities Russian Federation in terms of the total citation index and first place (more than 1.5 times higher than the indicator of the institute that took second place) among the institutes of the Division of Biological Sciences of the Russian Academy of Sciences (data from the scientific.ru network resource, supported by the Russian Foundation for Basic Research).

During the existence of the Institute, the work of employees in the field of fundamental science was awarded with two Lenin and eight State Prizes, the Demidov Prize, the Prize of the Federation of European Biochemical Societies (FEBS), several prizes of the Council of Ministers of the USSR and the USSR Academy of Sciences, the Gold Medal named after. M.V. Lomonosov, three Gold medals named after. G. Mendel (Czechoslovakia), a large Silver medal from the University of Heidelberg (Germany), three Gold medals and the RAS Prize named after. V.A. Engelhardt, RAS Prize named after. A.A. Baev and a number of other awards. Young scientists of the Institute received five Lenin Komsomol awards, the State Prize of the Russian Federation in the field of science and technology and the Gold Medal of the Russian Academy of Sciences.

In 2000-2005 Institute staff have received the awards listed below.

State Prize of the Russian Federation in the field of science and technology for young scientists (2004, D.A. Gryadunov, S.A. Lapa). Gold medal named after V.A. Engelhardt RAS (2004, L.L. Kiselev). Order of the Palm, France (2004, A.D. Mirzabekov). Prize of the German Society of Biochemists and Molecular Biologists “Prize Molecular Bioanalytics” (2004, A.D. Mirzabekov). Prize named after A.A. Baeva RAS (2004, A.V. Zelenin, E.D. Badaeva, O.V. Muravenko). Gold medal of the Russian Academy of Sciences for young scientists (2003, M.A. Zakharov). Gold medal of the World Exhibition of Innovations and Inventions “Eureka” (2001, Brussels, Y.M. Evdokimov, S.G. Skuridin, V.I. Salyanov, M.A. Zakharov). Grand Prix of the Russian Innovation Competition (2003, Yu.M. Evdokimov, S.G. Skuridin, V.I. Salyanov, M.A. Zakharov). Three awards from the Foundation for the Promotion of Russian Science (2002-2004: E.B. Khomyakova, D.A. Gryadunov, N.Yu. Oparina).

Over the past five years, the Institute has been actively involved in the implementation of various Federal scientific programs and programs of the Presidium of the Russian Academy of Sciences in the field of fundamental research. These include the programs “Human Genome” (until 2002), “Physico-chemical foundations of biology and biotechnology” (2001), “Cell biology, including stem cells” (2002), “Physico-chemical biology” (2003, since 2004 “Molecular and cellular biology”), “Fundamental sciences - medicine”, “Dynamics of gene pools of plants, animals and humans”, “Research and development in priority areas of development of science and technology for 2002-2006 .", "Government support for integration higher education and fundamental science."

The Institute's employees used fundamental scientific developments in applied fields. Such work includes research on genomic fingerprinting, which made it possible to carry out genetic identification of the remains of Emperor Nicholas II and members of his family; work on biological microchips and biosensors, new drugs against AIDS (Nikavir) and a number of others. These developments were repeatedly exhibited at Russian and international scientific and industrial exhibitions and received Gold medals and Grand Prix. Since 2003, medical diagnostics based on biological microchips, developed by the Institute’s staff, have been used in clinical practice to determine drug-resistant forms of tuberculosis, various forms of leukemia and other diseases.

To protect their intellectual property, Institute employees patent the results of scientific research. For 1985-2002 25 patents of the USSR and the Russian Federation, two US patents, 4 trademark certificates and one patent each from Japan, Sweden and South Korea were received. Currently, another 12 applications are being patented abroad.

The Institute's research work largely depends on financial support from various foundations. The Institute's employees annually receive about 100 grants from Russian and foreign scientific foundations. Among them: RFBR, ISCC (ISCC), INTAS, Howard Hughes Medical Institute (HHMI) and others. Since 2002, the Institute has introduced its own scientific scholarships for young scientists. Based on competitive selection, 4 people received them in 2003, 9 people in 2004, and 10 people in 2005.

The Institute trains scientific personnel in the field of molecular biology. In 2005, 56 graduate students are studying full-time at the Institute. In addition, the Institute has a Center for training specialists in the field of molecular biology, biophysics, and bioinformatics. There are three Centers for Collective Use at the Institute. Six employees of the Institute receive government support as heads of leading scientific schools. In 2000-2004 62 candidate and 8 doctoral dissertations were defended at the Dissertation Council. In total, since 1983, more than 400 candidate and more than 50 doctoral dissertations have been defended at the Institute. 18 employees are teaching at various universities in Moscow (MSU, MIPT, Moscow state academy fine chemical technology named after. M.V. Lomonosov, Russian State Medical University named after. N.I. Pirogov).

The Institute is characterized by extensive international scientific cooperation. Examples of such cooperation include traditional, sometimes decades-long, joint research with scientists from Germany, France, Italy, Great Britain, the USA, Sweden, Norway, Japan and a number of other countries. The Russian-French laboratory for the development of high-resolution technologies in the field of proteomics was created (2003-2006).

The International Engelhardt Conferences on Molecular Biology, which the Institute has held in Russia since 1992, also contribute to strengthening scientific ties. In December 2004, with the support of the Russian Academy of Sciences, the Ministry of Education and Science of the Russian Federation, the Russian Foundation for Basic Research, UNESCO and other organizations, the Institute held the seventh conference in Suzdal, dedicated to the 110th anniversary of the birth of V.A. Engelhardt. About 200 scientists from Russia, the USA, France, Germany, Italy, Sweden and Austria took part in it. The conference program included the following topics: 1. Functional genomics. 2. Protein synthesis. 3. Transcription. Molecular medicine. 4. Proteins: structure and function. 44 scientific reports were made, 63 works were presented at poster sessions.

The Institute is a co-founder of the leading Russian journal on molecular biology “Molecular Biology”. The editor-in-chief of the magazine from its founding until 1984 was V.A. Engelhardt, from 1985 to 1996 academician A.D. Mirzabekov, from 1996 to the present this post has been held by academician L.L. Kiselev. The high scientific authority of the journal is evidenced by the fact that the journal is also published in English. A number of institute employees are editors and members of the editorial boards of leading domestic and foreign scientific journals: “Molecular Biology”, “Bioorganic Chemistry”, “Biochemistry”, “Biophysics”, “Molecular Medicine”, “Immunology”, “Biological Membranes”, “Ontogenesis” , "Cytology". "Man", "Sensory Systems", "Liquid Crystals", "FEBS Letters", "Biochemie", "Folia Biologica", "Immunology Letters", "Biosensor and Bioelectronics",

The Institute has a scientific library (a branch of the Library of Natural Sciences of the Russian Academy of Sciences), which has about 80,000 items, receives 43 domestic periodicals and about 30 foreign ones.

The Institute’s employees actively promote the achievements modern science, appear on television and radio, publish their publications and interviews in periodicals and popular science press both in our country and abroad.

Continuing their creative growth, many former employees of the Institute became organizers and managers of leading laboratories, research centers and institutes in Russia and abroad, and occupy responsible positions in academic, government and commercial structures. Academician G.P. developed as scientists at the IMB and worked for more than 20 years. Georgiev - organizer and director of the Institute of Gene Biology of the Russian Academy of Sciences; Academician of the Russian Academy of Agricultural Sciences K.G. Scriabin - organizer and director of the Bioengineering Center of the Russian Academy of Sciences; Corresponding member RAS E.S. Severin - organizer and director of the Center for Medical Diagnostics; Academician M.P. Kirpichnikov - Minister of Science of the Russian Federation, Head. department, vice-rector of Moscow State University; Corresponding member RAS A.P. Ryskov - head. lab. IBG RAS; Corresponding member RAS N.V. Gnuchev - deputy Director of IBG RAS; Corresponding member RAS A.G. Gabibov - head lab. IBCh RAS; prof. O.O. Favorova - head Department of Moscow State Medical University.

The Institute's staff actively participates in the work of international organizations and editorial boards. Academician L.L. Kiselev is a member of the European Academy, the European Molecular Biological Organization (EMBO), the international organization HUGO, the editorial boards of the journals “FEBS Letters” and “Biochimie”; acad. Yu.V. Ilyin is a member of the European Academy; Corresponding Member RAS A.A. Makarov is a member of the European Calcium Society; Corresponding Member RAS S.A. Nedospasov is a member of the editorial board of the journal Immunology Letters; prof. P.M. Chumakov is a member of the editorial board of the journal “Oncogene”; prof. Yu.M. Evdokimov is a member of the editorial board of the journal “Biosensor and Bioelectronics”; prof. IN AND. Ivanov is a member of the editorial board of the journal J. Biomol. Structure & Dynamics".

On March 26, 2003, a ceremonial meeting of the Academic Council was held at the Institute, dedicated to the centenary of the birth of Corresponding Member of the USSR Academy of Medical Sciences Alexandra Alekseevna Prokofieva-Belgovskaya (1903-1984).

In July 2003, the director of the Institute, academician Andrei Darievich Mirzabekov, the author of a number of fundamental discoveries in molecular biology, passed away. His research on the structure of transport ribonucleic acids and chromatin and the creation of biological microchips is widely known. His directorship came during difficult years for Russian science, but the Institute’s scientific staff was preserved. In 1999, summing up the past century, the American newspaper The Sunday Times named A.D. Mirzabekova is among the most outstanding scientists of the 20th century.

In 2004, the scientific community widely celebrated the 100th anniversary of the birth of Academician Alexander Aleksandrovich Baev (1904-1994). On January 19-21, 2004, the All-Russian conference “From the double helix to the human genome” dedicated to this event was held at the Institute. The conference opened with a ceremonial meeting dedicated to scientific activity A.A. Baev, which was attended by the President of the Russian Academy of Sciences, Academician Yu.S. Osipov, Minister of Education and Science A.A. Fursenko, Vice-President of the Russian Academy of Sciences, Academician N.A. Plate, academicians R.V. Petrov and L.L. Kiselev, Academician of the Russian Academy of Agricultural Sciences K.G. Scriabin, corresponding member of the RAS A.A. Makarov. The Bay Memorial Lecture: “Importance of biotechnology for the XXI century” was given by the famous Belgian scientist, Professor M. Van Montagu. The scientific program of the conference included the following sections: functional and evolutionary genomics; plant genomics; medical genomics; ethnogenomics; spatial organization of the genome; genomics: new methodologies. At the conference there was " round table"Principles of organization of the mitotic chromosome and structural features of its individual sections."

A.A. A special memorial session was dedicated to Baev at the First All-Russian Congress of the Society of Biotechnologists of Russia, which was held in June 2004 in Kazan. On one of the buildings of Kazan University, which A.A. graduated from in 1927. Baev, a memorial plaque has been unveiled.

In 2002, the Russian Academy of Sciences established the Prize named after. A.A. Baev "For outstanding work in the field of genomics and gene informatics." In 2004, the first laureates of this prize for the series of works “Genome-chromosomal analysis of higher organisms” were employees of the Institute: Professor A.V. Zelenin, Doctor of Biological Sciences E.D. Badaeva, Ph.D. O.V. Muravenko.

In conclusion, it is necessary to mention one more event that has become traditional for the Institute and the scientific community of Moscow. Since 1985, paying tribute to the memory and respect of V.A. Engelhardt, on his birthday - December 4, a prominent domestic or foreign scientist gives a memorial Engelhardt lecture at the Institute on topical problems of biochemistry and molecular biology.

Grant Information

17-04-01318; “Cellular mechanisms of pathology of the ascending aorta and aortic valve”; leader Malashicheva A. B.

The work is devoted to the search for molecular links involved in the pathogenesis of aneurysm of the ascending thoracic aorta and calcification of the aortic valve - common and dangerous cardiovascular diseases in humans.

Based on the analysis of published data, a hypothesis has been put forward that disruption of the functioning of the main signaling pathways TGF-beta, Notch, BMP can lead to disruption of signal transduction pathways in the cells of the aorta and aortic valve during aneurysm and calcification of the aortic valve, to changes in the expression of the regulatory elements of the corresponding signaling pathways. To test this hypothesis, several types of vascular cells and valve cells will be compared from healthy donors and patients with ascending thoracic aortic aneurysm or aortic valve calcification in terms of the activity of the TGF-beta, Notch, and BMP signaling pathways.

Based on the results obtained, conclusions will be drawn about the role of altered activity of these signaling pathways and cellular mechanisms in the pathogenesis of aneurysms of the ascending thoracic aorta and aortic valve calcification.

18-315-00177; “Studying the role of extracellular mitochondrial DNA and microRNA in the development of inflammation and fibrofatty replacement of the myocardium”; head Khudyakov A. A.

The processes of inflammation, fibrosis and fatty replacement of the myocardium are a common cause of heart failure and sudden cardiac arrest. Despite the significant amount of accumulated data, the reasons for these changes have not yet been established.

Recently, there has been an increase in the number of studies devoted to biologically active molecules released by cells into the extracellular environment, in particular mitochondrial DNA (mtDNA) and microRNA. Extracellular mtDNA is a strong inducer of inflammation, and secreted microRNAs, penetrating into cells, are able to regulate the expression of their genes, triggering physiological and pathological processes.

The goal of the presented project is a comparative assessment of the qualitative and quantitative composition of extracellular mtDNA and microRNA in biological samples from patients with arrhythmogenic cardiomyopathy and healthy donors.

As a result of the presented project, the content of extracellular mtDNA and microRNA will be studied in various fractions of the culture medium of cardiomyocytes differentiated from patient-specific induced pluripotent stem cells and fractions of pericardial fluid of patients with arrhythmogenic cardiomyopathy and the control group. Will be fulfilled comparative analysis content of extracellular mtDNA and microRNAs, an assessment of the immunogenicity of extracellular mtDNA and a bioinformatic search for targets of identified extracellular microRNAs among signaling cascades. The results obtained will allow us to formulate hypotheses about the role of mtDNA and microRNA in the processes of inflammation, fibrosis and fat replacement and develop diagnostic approaches using pericardial fluid.

18-34-00277; “Notch-dependent mechanisms of intercellular interactions of endothelial and mesenchymal cells”; head Kostina A.S.

The project is dedicated to studying the interaction between endothelial and mesenchymal cells. Using co-culture of endothelial and mesenchymal cells, the influence of cell-cell interactions on the induction of osteogenic and smooth muscle differentiation will be studied. The role of the Notch signaling pathway in the induction of cell differentiation will be analyzed as the main signaling pathway responsible for the communication of endothelial cells with underlying cells of mesenchymal origin. The project will use primary human endothelial cells from various sources: umbilical vein, aorta, aortic valve, and primary human cells of mesenchymal origin: mesenchymal stem cells of adipose tissue, smooth muscle cells of the aorta, interstitial cells of the aortic valve. The results obtained will allow us to draw conclusions about the role of the interaction of endothelial cells with cells of mesenchymal origin, as well as the contribution of activation of the Notch signaling pathway to the process of differentiation of mesenchymal cells.

18-29-17074; “Nanofibrous 3D scaffolds based on polysaccharides for tissue engineering”; head Skorik Yu. A.

The creation of materials with specified properties is an urgent task of modern chemistry and materials science. This project is devoted to the development and creation of non-woven scaffolds for cell growth based on natural biocompatible and bioresorbable polysaccharides obtained by electrospinning.

Today, electrospinning nanofibers from polymer solutions is one of the most common methods for obtaining nanosized matrices for various applications. The diameter of the resulting nanofibers corresponds to the size of the intercellular matrix. One approach to regulating the properties of final materials is to obtain composite materials based on a mixture of polymers or a polymer matrix with a nanofiller. The composite material has the properties of both components.

This project involves the production of composite nonwoven scaffolds by sequential molding of biopolymer solutions, as well as molding a mixture of biopolymer solutions with chitin nanofibrils, multilayer ones based on a combination of layers of polyacids and chitosan, and modification of fibers by introducing a nanofiller - modified nanoparticles (nanofibrils) of chitin - into the molding solutions. The physicochemical properties of the resulting scaffolds (water-holding capacity and strength properties), as well as their general toxicity, effect on cell adhesion and proliferation will be studied. It is planned to study the influence of electrostatic interactions between polymers and nanofiller and the formation of PEC on the electrospinning process and the properties of scaffolds.

18-315-20050; “Development of a method for studying the neurogenic regulation of the pulmonary circulation and remodeling of the pulmonary artery and substantiation of a new method of treating pulmonary hypertension by selective action on nerve elements”; head Mikhailov E. N.

The vessels of the lungs are innervated by sympathetic and parasympathetic nerve fibers. Located predominantly in the proximal parts of the pulmonary artery, sympathetic nerve fibers influence the magnitude of pulmonary vascular resistance and the compliance (stiffness) of the pulmonary artery. The above indicators are closely related to the severity of hemodynamic disorders and prognosis for pulmonary hypertension.

Pilot studies have shown that a sign that indirectly reflects changes in the structure and innervation of the vessels of the pulmonary circulation can be a reaction to electrical stimulation of the pulmonary artery. The severity of this reaction depends on the density of nerve endings and the tone of the sympathetic nervous system. In turn, changes in vasomotor reactions may be a reflection of structural changes in the vascular wall. The purpose of this study is to study the vasomotor reactions of the vessels of the pulmonary circulation and the mechanisms of their implementation in response to electrical stimulation of the pulmonary artery, as well as to establish the connection of autonomic reactions with structural changes in the pulmonary artery under normal conditions and in conditions of pulmonary hypertension.

Based on the results of the study, it is planned to obtain the basic prerequisites necessary for the development of a treatment method using selective denervation of the pulmonary artery.

19-015-00313; “Mechanisms of lamin A participation in stem cell differentiation”; head Kostareva A.A.

The project is aimed at solving a fundamental problem in developmental biology and medicine - studying the role of A/C type lamin proteins in cell differentiation. The goal of the project is to study the mechanisms of lamin A participation in cell differentiation.

Resident mesenchymal stem cells and induced pluripotent stem cells will be used, with modeled mutations in the lamin A/C gene, or obtained directly from patients with verified laminopathy and mutations in the lamin A/C gene. The interaction of lamin A with intracellular signaling pathways mediating cell differentiation will be studied. It is expected to evaluate which signaling pathways are involved in the interaction with lamin A during cell differentiation. Stem cell lines (mesenchymal and induced pluripotent) will be obtained from patients with verified mutations in the LMNA gene and clinically confirmed laminopathy. The operation of mutant lamin in cells will also be modeled by introducing a mutant gene on a lentiviral carrier into primary cultures of cells of mesenchymal origin. When differentiation in the adipogenic, osteogenic or cardiogenic direction is started, the activation/inactivation of the Wnt, Notch, TGF-beta, BMP signaling pathways will be assessed in depending on the presence/absence of a mutation in the LMNA gene, and thus the signaling pathways and genes with which lamin A interacts during differentiation were identified.

19-29-01066; “Methods for analyzing large unstructured data to develop a system for assessing the prognosis of restoration of integrative brain function and creating treatment methods in conditions of impaired consciousness - a combination of loss and new pathological integration of the body”; head Kondratyeva E. A.

The proposed scientific research is based on the following hypothesis: consciousness is the result of the integrative activity of the whole organism. In the absence of consciousness, functional systems both realizing the phenomenon of consciousness (for example, motor systems) and ensuring the maintenance of adequate molecular-cellular vital activity of the brain (from the cardiovascular to the immune systems of the body) fall out of such generation. Impaired consciousness, depending on its severity, is clinically manifested by loss of functions. But such dropouts are always accompanied by a new organization (integration) of the remaining functions. The complete loss of such an organization (brain death) is currently legally recognized as the biological death of the organism.

The work is intended to study various options integration of the body in case of impaired consciousness. Based on the analysis of stable conditions recorded in the medical history in medical information systems: data from clinical studies, intrascopic with functional programs, neuroendocrine, brain metabolomes, genetic, new, more sensitive and specific methods for predicting outcome, and the possibility of higher organization of functions will be developed. Identification of variants of the pathological organization of the body's vital functions in these patients (allostasis) will serve as the basis for the development of new treatment methods. Based on the analysis of semi-structured data from electronic medical systems using machine learning methods, it is possible to predict clinical events, as well as analyze and interpret stable brain states based on heterogeneous, semi-structured medical data.

17-15-01292; “Structural and molecular mechanisms of Nav1.5 channel dysfunction in the myocardium”; head Zhorov B.S. (responsible executive - Kostareva A.A.)

Heart rhythm disturbances are an important medical problem. In many cases, rhythm disturbances are caused by inherited or de-novo mutations in the Nav1.5 sodium channel, which is responsible for the initial (0) phase of the action potential in cardiomyocytes. The primary goal of this project is to better understand the structural molecular mechanisms that underlie sodium channelopathies in the myocardium.

Hereditary mutations in the channels cause pathological conditions - channelopathies. In particular, mutations in the Nav1.5 and Nav1.1/Nav1.2 channels cause heart rhythm disorders and epilepsy, respectively. The project will include sequencing of Nav1.5 (SCN5A) genes in patients with heart rhythm disorders. Data from these experiments will be analyzed by bioinformatics methods in order to identify mutations potentially responsible for disturbances in the properties of the Nav1.5 channel. The most likely candidate mutations will be examined in Nav1.5 homology models constructed using recent X-ray and cryoelectron microscopy structures of homologous sodium, calcium and potassium channels. Channel state-dependent contacts will be identified and analyzed by comparing Monte Carlo energy-minimized models of the closed and open states of Nav1.5 and the corresponding mutants. The hypotheses will be tested by expressing in HEK-293 or CHO-K1 cells mutant forms of Nav1.5 putative to cause channelopathies, as well as Nav1.5 with mutations in channel-dependent contacts, analyzing the electrophysiological properties of the mutants, and comparing them with those of the wild-type channel. .

17-75-30052; “Development of personalized therapy for obesity and type 2 diabetes mellitus to reduce cardiovascular risks”; Head Shlyakhto E.V. (responsible executive - Babenko A.Yu.)

Type 2 diabetes mellitus (T2DM), which develops mainly against the background of visceral obesity, is a socially significant disease, the reduction of losses from which is a priority in the development of modern medicine. The transition to a personalized choice of therapy is the main way to solve this problem.

In modern algorithms, decision-making on the choice of treatment for both obesity and T2DM is based on the selection of “ideal candidates” for one or another treatment option, which is not always effective, since it does not take into account psychological characteristics, type of eating behavior, genetic predictors, the functional state of the insular apparatus and the level of hormones that regulate carbohydrate metabolism, the comfort of each type of treatment for the patient. This affects not only the effectiveness, but also the adherence of patients to therapy, and the long-term maintenance of target parameters, which determines the cardiovascular prognosis. Creating an analytical program/decision-making technology based on the maximum amount of data and taking into account the listed features and predictors of response to therapy, as well as taking into account the dynamics of plastic molecular genetic markers reflecting the impact of the chosen therapy option on the cardiovascular system, will most likely allow achieve target indicators with maximum improvement in cardiovascular prognosis and, while maintaining treatment safety, will ensure personalization of treatment. The implementation of the project will allow for the most rational use of medications, minimizing the number of errors when choosing treatment.

18-14-00152; “Molecular genetic mechanisms of calcification of the heart and blood vessels”; leader Malashicheva A. B.

The project is aimed at elucidating the early mechanisms of activation of osteogenic differentiation, leading to calcification of cardiac and vascular tissues. Bone formation and pathological calcification of cardiac and vascular tissues have similar features, especially in advanced stages. The triggering mechanisms that lead to pathological calcification of the heart and blood vessels remain largely unexplored, and early markers of osteogenesis unknown. Calcification of heart valves is a common cardiovascular complication, and to date there is no conservative treatment for this pathology. The mechanisms of valve and aortic calcification remain unclear. The goal of this project is to identify the molecular cellular and genetic mechanisms leading to the induction of osteogenic differentiation in the tissues of the aortic valve of the heart and aorta. The project involves the use of interstitial and endothelial cells of the aortic valve, endothelial and smooth muscle cells of the aorta, as well as mesenchymal multipotent stromal cells of adipose tissue. During the project, early molecular markers of osteogenic differentiation will be identified in the cell systems being studied; the role of intercellular interactions in the induction of pro-osteogenic genes will be clarified; the role of a number of signaling pathways in the induction of osteogenic differentiation was analyzed; A comparison was made of cells obtained from healthy people and from patients with aortic valve calcification in terms of the ability of these cells to osteogenic differentiation. The role of purinergic signaling in the induction of osteogenesis in aortic valve cells will be studied; The role of the extracellular matrix in the induction of osteogenic cell differentiation will be investigated. Using next-generation sequencing of a cohort of patients with aortic valve calcification, the contribution of the genetic component to the occurrence of calcification will be assessed. Such an integrated approach will provide fundamentally new knowledge about the mechanisms of initiation of calcification and osteogenic differentiation processes in health and disease. The plan of the proposed project received approval from the local ethics committee of the National Medical Research Center named after. V. A. Almazova. All studies involving individuals will be held in accordance with the Declaration of Helsinki. The implementation of this project will allow us to draw conclusions about the early initiating mechanisms of calcification of the aortic valve and aorta, the similarities or differences of this process in the cells of the valve and aorta with osteogenic differentiation of mesenchymal multipotent stromal stem cells, the role of signaling pathways associated with the induction of osteogenesis, the role of purinergic signaling in activation pro-osteogenic mechanisms in normal and pathological conditions. Obtaining such data is important for understanding the fundamental mechanisms of initiation of osteogenic differentiation, both in order to prevent such differentiation and to activate it in corresponding pathologies.

16-15-10178; “Study of the mechanisms of impaired regeneration of skeletal muscles and pathological replacement of functional muscle tissue with fatty tissue”; head Dmitrieva R.I.

Identification of the molecular mechanisms regulating the pathological replacement of functional muscle tissue with adipose tissue still remains a serious unsolved problem in fundamental medicine.

The main hypothesis that we are testing in this project is the assumption that the development of adipose and muscle tissue is regulated in concert; adipogenic and myogenic signaling pathways are upregulated during normal development and growth of skeletal muscle and in diseases characterized by pathological replacement of functional skeletal muscle tissue with adipose tissue. , the balance of stimulation of adipogenic and myogenic signaling pathways is disrupted. The hypothesis was formed during the work on project No16-15-10178, as a result of which we obtained new data on the coordinated regulation of myogenic and adipogenic transcriptional programs during the development and regeneration of skeletal muscles. The results obtained for the mouse myoblast cell line C2C12 were generally confirmed by studies using primary cultures of mouse muscle satellite cells, as well as human muscle satellite cells and human muscle mesenchymal progenitors.

In this project, we plan to overcome this shortcoming by generating a reproducible model of muscle differentiation from human induced polypotent cells (iPSCs). The iPSC model of muscle differentiation will be obtained from mononuclear cells of patients with muscular dystrophies caused by mutations in the genes encoding proteins of the LINC complex. iPSC samples from healthy donors were previously obtained at our institute and are stored in the Center's biobank.

The second line of research was also formed on the basis of data we received during the implementation of project No. 16-15-10178. Data suggest that the R482L mutation of the lamin gene stimulates the formation of fat depots in myoblasts and myotubes while causing muscle fiber hypertrophy, which is consistent with the diversity of muscle pathology phenotypes in patients with familial partial Dunningan lipodystrophy (FPLD2). Therefore, in this project we plan to study the role of changes in the structure of LMNA-DNA regulatory complexes caused by the LMNA-R482L mutation and to identify the mechanisms of fatty degeneration in FPLD2. This series of experiments will be performed using C2C12 mouse myoblasts genetically modified with LMNA-R482L lentiviral constructs.

17-75-10125; “Study of the role of the synemin gene (SYNM) in the differentiation of mesenchymal stromal cells and the formation of congenital malformations”; head Zlotina A.M.

Intermediate filament proteins are a large group of cytoskeletal proteins involved in maintaining the structural and mechanical integrity of the cell, as well as being involved in a number of other key cellular functions. It is known that defects in intermediate filament genes can lead to the development of severe hereditary pathologies, many of which affect tissues of mesenchymal origin, including myopathies and cardiomyopathies, lipodystrophies, some skeletal pathologies, and complex syndromic combinations.

This project aims to study the role of the SYNM gene, encoding the intermediate filament synemin, in the differentiation of multipotent mesenchymal stromal cells and to study the functional significance of its genetic variants. In particular, the data obtained will allow us to evaluate the effect of a previously uncharacterized genetic variant of sinemen, which we identified in a patient with the ulnar-mammary syndrome phenotype, on the differentiation of stromal mesenchymal cells, which will help expand our understanding of the molecular cellular mechanisms of the development of complex birth defects affecting tissues of mesenchymal origin , as well as the range of clinical pathologies associated with mutations in intermediate filament genes.

18-75-10042; “Studying predictors of postprandial glycemic response and the need for insulin therapy in women with gestational diabetes mellitus in order to personalize approaches to its treatment”; head Pustozerov E. A.

The purpose of the work is to study predictors of postprandial glycemic response (PPG) and the need for insulin therapy in women with gestational diabetes mellitus (GDM) in order to personalize treatment approaches and create an interactive mobile application for women with GDM. Stage I – study of predictors, construction and testing of models for predicting PPGO and the need for insulin therapy in women with GDM; development of an interactive mobile application for women with GDM.

Stage II – randomized controlled trial of the use of an interactive mobile application for women with GDM.

It is planned: to create a database of patients with GDM based on completed electronic self-monitoring diaries; validate electronic food diaries based on daily excretion of biomarkers in urine; to study the composition of the intestinal microbiome in women with GDM and women with normal glucose tolerance; examine the contribution of gut microbiome characteristics to PPGO; to study the role of genetic variations in genes regulating insulin secretion and associated with insulin resistance in predicting PPGO; to study the role of genetic variations in genes regulating insulin secretion and associated with insulin resistance, and characteristics of the intestinal microbiome in predicting the need for insulin therapy in women with GDM; build models for predicting PPGO in women with GDM at different stages of pregnancy; develop an interactive mobile application with built-in formulas for predicting PPGO in real time; conduct a randomized trial of the effect of using an interactive mobile application on glycemic control in women with GDM and pregnancy outcomes.

18-75-00006; “Study of the association of rare and shortening variants in the titin gene with the course of post-infarction myocardial remodeling”; head Kiselev A.M.

The goal of this project is to identify rare and truncating variants of the titin gene that may affect the course of post-infarction myocardial remodeling. The study will be conducted on a ready-to-analyse, described and characterized group consisting of patients who have suffered acute myocardial infarction (600 patients). The topic of post-infarction remodeling and identification of genes responsible for this process has recently attracted a large number of researchers. Several studies have been published describing pathogenic variants of various structural, z-disc-associated and regulatory genes in connection with myocardial dilatation. Among them, much attention is paid to the effect of shortening variants of the titin gene on the course of various cardiac diseases. The presence of such variants in 2-4% of a relatively healthy population may indicate the absence of their direct pathogenic effect on the course of the disease. However, studies showing a significant connection and studying the effect of shortening variants of titin with dilatation of the heart chambers against the background of the condition after acute myocardial infarction have not yet been conducted.

The main objective of the project is to study the association of shortening and rare pathogenic variants of the titin gene and the course of post-infarction myocardial remodeling. To accomplish this task, next-generation sequencing technologies with targeted enrichment and bioinformatics methods of data analysis will be used. Special attention will be paid to statistical processing of the obtained data and identifying relationships between the presence of shortening and rare pathogenic variants of the titin gene and the development of myocardial dilatation associated with post-infarction remodeling. Based on the data obtained, conclusions will be drawn about the relationship between the presence of rare and shortening variants of the titin gene and the risk of developing dilatation and chronic heart failure in patients who have suffered acute myocardial infarction. The scientific novelty of the presented project is determined by the fact that:

1) There are no studies in the literature that would reveal the relationship between shortening and rare variants of the titin gene and the development of post-infarction myocardial remodeling.

2) The data obtained along with modern technologies Genetic testing will allow us to develop personalized approaches to the treatment of patients who have suffered acute myocardial infarction. 3) The data obtained will create the basis for future functional studies of the relationship between the presence of rare and shortening titin variants and the pathogenesis of various cardiac diseases.

19-75-20076; “Molecular basis for the participation of subpopulations of extracellular vesicles in the development of a systemic inflammatory response initiated by damage to elements of the cardiovascular system”; head Golovkin A.S.

The project is aimed at studying the mechanisms of regulation through extracellular vesicles of the systemic inflammatory response (SIR), which develops when elements of the cardiovascular system are damaged. The specific objective of the project is to characterize (phenotype, molecular composition, immunogenic properties) subpopulations of extracellular vesicles circulating in the blood during damage to elements of the cardiovascular system and assess their contribution to the regulation of the systemic inflammatory response. The urgency of the problem is determined by the prevalence of cardiovascular diseases, which are the leading cause of death and disability in the world. And also the key role of the systemic inflammatory response, which develops in response to damage and determines the further course of the disease, its complications and outcomes. The study will examine two groups of patients undergoing coronary artery bypass grafting (CABG) with and without cardiopulmonary bypass (CPB), animal models of myocardial ischemia-reperfusion injury (rats) and cryoinjury (Danio rerio), and (Danio rerio) and cellular (human monocyte culture THP-1) models of the development of the immune response. The scientific novelty of the project lies in the application of an integrated approach that combines modern methods molecular and cellular biology, clinical and experimental medicine for a detailed study of extracellular vesicles in unique samples of biological material from patients and several model systems. High-resolution flow cytometry will be used to study the heterogeneity of the population of circulating extracellular vesicles, based on the presence of a certain set of surface markers in their composition, and targeted immunosorting will allow assessing the molecular composition, immunogenicity and contribution to pathogenesis of individual vesicle subpopulations. The properties of specific vesicle subpopulations will be determined through the detection of biomolecules within them, including quantitative analysis of mitochondrial DNA and microRNA, as well as large-scale profiling of short RNA levels using next-generation sequencing. Functional analysis of the immunogenic properties of vesicle subpopulations will be carried out both in vitro and in vivo in the Danio rerio model of the immune response. Analysis of the phenotypes, molecular composition and immunogenic properties of extracellular vesicles circulating in the blood at various stages damage to elements of the cardiovascular system will determine their role in the regulation of the systemic inflammatory response, as well as obtain information about biomarkers of complicated and uncomplicated course of SVO and potential therapeutic targets.

19-75-00070; “The role of GSK3B kinase in remodeling the structure of intercalary discs of cardiomyocytes in normal and pathological conditions”; head Khudyakov A. A.

Cardiomyocyte intercalary discs are necessary to form a strong mechanical connection between cardiomyocytes and ensure electrical conductivity of myocardial tissue. Recently, interest in the structure and function of intercalary discs has increased significantly, as it has been discovered that intercalary discs act as mechanosensors and are also involved in intracellular signaling. More than two hundred proteins are known to be associated with intercalated discs, changes in which lead to the development of heart diseases, the most common of which is arrhythmogenic cardiomyopathy, a genetically and phenotypically heterogeneous disease. The diversity of genetic determinants leading to the development of a similar disease phenotype suggests that changes at the molecular level can be initiated in different compartments of the cell, but subsequently lead to disruption of the structure of intercalated discs, which is characteristic of arrhythmogenic cardiomyopathy. One of the candidates for the role of a signal carrier between the intercalary disc and the intracellular space is GSK3B kinase. There is evidence that GSK3B kinase inhibitors are able to prevent the development of arrhythmogenic cardiomyopathy in animal models, but the detailed molecular mechanisms of this effect remain unexplored.

This study is aimed at studying the role of GSK3B kinase in regulating the structure of the intercalated disc in normal conditions and in arrhythmogenic cardiomyopathy. Particular attention is planned to be paid to ion channels associated with the intercalary disk, and electrical function cardiomyocyte. The study will conduct a genetic study of patients with arrhythmogenic cardiomyopathy, obtain patient-specific induced pluripotent cells and, using cardiomyocytes differentiated from induced pluripotent stem cells, test hypotheses about the influence of GSK3B activation and inhibition on the electrophysiological characteristics of cardiomyocytes and study the role of GSK3B in the regulation of transport and membrane localization of individual components of intercalated disks.

075-15-2019-161; “Development of personalized approaches to the treatment of arterial hypertension, taking into account molecular genetic and cytokine markers, neurogenic influences, organ damage and metabolic disorders”; head Konradi A. O.

The project is dedicated to studying the mechanisms for increasing the level blood pressure and subclinical damage to target organs in obesity at the molecular genetic and cellular levels with the search for new targets and translation of the results of experimental studies into the clinic.

It seems promising to study the role of biologically active peptides produced by adipose tissue - cytokines (adipokines), as well as the influence of increased activity of the sympathetic nervous system. Two ion channels were selected as potential cellular targets of adipokines: the cation channel TRPC and the epithelial sodium channel ENaC. Presumably, these channels may be the target of adipokines and are involved in the development of subclinical target organ damage and arterial hypertension in obesity.

The project will study the role of adipokines in the regulation of TRPC channels in podocytes of nephron glomeruli and ENaC of the distal nephron. It is planned to evaluate changes in the functional activity of channels in podocytes of nephron glomeruli and in cells of the distal nephron under the influence of selected adipokines. A promising molecular genetic marker of obesity and adipose tissue distribution is the FTO gene, namely carriage of the A allele of the rs9939609 polymorphism of the FTO gene. Adipose tissue distribution may play an important role in maintaining metabolic health in obese patients. The project will be the first to evaluate changes in various parameters and factors with a decrease in sympathetic nervous system activity in a prospective follow-up of obese patients with resistant hypertension who underwent radiofrequency ablation of the renal sympathetic nerves.

Selected publications

1. Kostareva A., Sjöberg G., Bruton J., Zhang S. J., Balogh J., Gudkova A., Hedberg B., Edström L., Westerblad H., Sejersen T.

Mice expressing L345P mutant desmin exhibits morphological and functional changes of skeletal and cardiac mitochondria.

2. Kostareva A., Gudkova A., Sjöberg G., Mörner S., Semernin E., Krutikov A., Shlyakhto E., Sejersen T.

Deletion in TNNI3 gene is associated with restrictive cardiomyopathy.

3. Anna Kostareva, Alexandra Gudkova, Gunnar Sjoberg, Ivan Kiselev, Olga Moiseeva, Elena Karelkina, Lev Goldfarb, Eugeniy Schlyakhto and Thomas Sejersen.

Desmin mutations in a St. Petersburg cohort of cardiomyopathies. Acta Myologica, 2006, 2006 Dec; 25 (3): 109-15.

4. Goudeau B., Rodrigues-Lima F., Fischer D., Casteras-Simon M., Sambuughin N., de Visser M., Laforet P., Ferrer X., Chapon F., Sjoberg G., Kostareva A. , Sejersen T., Dalakas M. C., Goldfarb L. G., Vicart P.

Variable pathogenic potentials of mutations located in the desmin alpha-helical domain. Hum Mutat. 2006 Sep; 27 (9): 906-13.

5. Bar H., Kostareva A., Sjoberg G., Sejersen T., Katus H. A., Herrmann H.

Forced expression of desmin and desmin mutants in cultured cells: impact of myopathic missense mutations in the central coiled-coil domain on network formation. Exp Cell Res. 2006 May 15; 312(9):1554-65. Epub 2006 Mar 7.

6. Bar H., Mucke N., Kostareva A., Sjoberg G., Aebi U., Herrmann H.

Severe muscle disease-causing desmin mutations interfere with in vitro filament assembly at distinct stages. Proc Natl Acad Sci U S A. 2005 Oct 18; 102 (42): 15099-104. Epub 2005 Oct 10.

7. Sjöberg G., Kostareva A., Sejersen T.

Lakartidningen. 2005 Mar 14-20; 102(11): 845-7, 850-3. Review. Swedish.

8. Grineva E., Babenko A., Vahrameeva N., Bogdanova M., Kostareva A., Popcova D., Larionova V.

Type 2 deiodinase Thr92Ala polymorphism impact on clinical course and myocardial remodeling in patients with Graves" disease. Cell Cycle. 2009: 15; 8 (16): 2565-9.

9. Malashicheva A., Kanzler B., Tolkunova E., Trono D., Tomilin A.

Lentivirus as a tool for lineage-specific gene manipulations. Genesis. July 2007; 45 (7): 456-459.

10. Tolkunova E., Malashicheva A., Parfenov V. N., Sustmann C., Grosschedl R., Tomilin A.

11. Aksoy I., Sakabedoyan C., Bourillot P. Y., Malashicheva A. B., Mancip J., Knoblauch K., Afanassieff M., Savatier P.

Self-renewal of murine embryonic stem cells is supported by the serine/threonine kinases pim-1 and pim-3. Stem Cells. 2007 Dec; 25 (12): 2996–3004.

12. Enukashvily N. I., Malashicheva A. B., Waisertreiger I. S.

Satellite DNA spatial localization and transcriptional activity in mouse embryonic E-14 and IOUD2 stem cells. Cytogenet Genome Res. 2009; 124 (3-4): 277-87. Epub 2009 Jun 25

13. Correia A. S., Anisimov S. V., Li J. Y., Brundin P.

Growth factors and feeder cells promote differentiation of human embryonic stem cells into dopaminergic neurons: a novel role for fibroblast growth factor-20. Front Neurosci. July 2008; 2 (1): 26-34. Epub 2008 Jul 7. PMID: 18982104 Related articlesFree article

USSR Academy of Sciences, the leading research institution in the field of molecular biology (See Molecular biology). Organized in 1957 (until 1965 - Institute of Radiation and Physico-Chemical Biology). The founder and director of the institute is V. A. Engelhardt. The main directions of research work: transmission and implementation of hereditary information, molecular mechanisms of protein biosynthesis, chemical and physical basis of enzyme action, connection of the structure of nucleic acids and proteins with their functions in the cell, macromolecular organization of chromosomes, development of physical methods for studying macromolecules. In M. b. And. the primary structure of two transport ribonucleic acids (tRNAs) has been deciphered; the theory of regulation of genome functioning in higher organisms was experimentally substantiated and formulated; for the first time in the USSR, the sequence of amino acids in a large molecule of the enzyme protein - aspartate aminotransferase was determined (together with the M. M. Shemyakin Institute of Bioorganic Chemistry of the USSR Academy of Sciences); new approaches to studying the structure of active centers of enzymes (inhibitory analysis) and functional regions of RNA (method of “cut molecules”) have been proposed; new methods for structural studies of proteins and nucleic acids have been developed. By the beginning of 1973 in M. b. And. there were 13 laboratories. Together with the Council on Problems of Molecular Biology of the USSR Academy of Sciences, the institute organizes international meetings and symposia. Works of M. b.’s employees. And. published in the journals: “Molecular Biology” (since 1967), “Biochemistry” (since 1936), “Cytology” (since 1959), “Reports of the USSR Academy of Sciences” (since 1933), “Biophysics” (since 1956), “Biochimica et Biophysica Acta" (N.Y. - Amst., since 1947), "FEBS Letters" (Amst., since 1968), "European Journal of Biochemistry" (V., since 1967), in collections and in the form of monographs.

Lit.: Institute of Molecular Biology, M., 1971.

M. Ya. Timofeeva.

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