Yuri Kotelevtsev

Yuri Kotelevtsev’s main expertise is in molecular genetics of cardiovascular disease and in gene targeting in embryonic stem cells.  He has provided a crucial contribution towards the discovery of the first genetic linkage between elevated blood pressure and angiotensinogen in essential hypertension in men.  He has also introduced several knockout and transgenic models of hypertension, metabolic syndrome and atherosclerosis, including knock out (KO) of 11  β−hydroxysteroid dehydrogenase type I (11β-HSD-1) gene. Resistance of 11β-HSD-1 knockout mice to obesity and stress established this gene as a drug target (see publication # 41 in the Publications tab). This publication initiated drug discovery programmes in the leading pharmaceutical  companies. Now the inhibitors of 11β-HSD-1 are in clinical trials for treatment of obesity, metabolic syndrome and dimentia. Genetic KO of 11β-HSD-2 produced a model of hypokalemia and hypertension.

Now Yuri is working on the proprietary double knockout (DKO) 11β-HSD-2/ApoE, a mouse strain featuring accelerated atheroma and heart failure. The focus of research is on identification of cell autonomous effects of 11β-HSD-2 mutation on pro inflammatory changes in endothelium leading to atherosclerosis. A patent application is pending for 11β-HSD-2/ApoE strain as a screening platform for new drugs targeting atheroma formation and heart failure.

Yuri’s work contributed towards understanding of the role of endothelin-1 in long term control of blood pressure, particularly in the role of endothelin receptor type B (ENRB) in the kidney medulla. In collaboration with Professor David Webb and Dr. Alan Bagnall he has accomplished modification of the ENRB gene with loxp sites and generated the mice with conditional tissue specific knockouts of ENRB. EC ENRB KO mice show susceptibility to pulmonary hypertension (in collaboration with Professor Mandy MacLean, Glasgow). Together with his collaborators in Utah (Professor Don Kohan, Salt Lake City) Yuri demonstrated that collecting duct specific knock out of ENRB leads to salt sensitive hypertension in mice. The work is now in progress on regulation of blood flow and tissue remodelling in endothelial and smooth muscle cell specific ENRB KO (funded by British Heart Foundation). Combination of tissue specific knockout and knockin lines with beta-galactosidase to trace expression of ENRB are used for localization of ENRB in the vasculature and epithelial cells in the medulla in the developing kidney.

Yuri’s research program at Skoltech will continue investigation of genesis and manifestations of metabolic syndrome resulting particularly in nonalcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD). The ultimate aim of his studies is the discovery of gene products and signaling pathways which can be manipulated to ameliorate low grade chronic inflammation which is a major driver of disease progression.

  • Liver fibrosis
    We have shown antifibrotic action of 4 methylumbelliferone (4MU), a hyaluronan synthase (HAS) inhibitor, in mouse model of liver fibrosis  (paper in preparation).  We are  investigating the cellular and molecular mechanisms of  hepatocyte injury and repair reactions leading to scar formation. This process involves macrophage activation, hepatic stellate cells differentiation to myofibroblasts, activation of matrix remodelling enzymes. 4 MU has a complex effect on these processes. Its integrative action causes diminished collagen and hyaluronan deposition. Our main goals are:
    – To establish screening platform for HAS inhibitors and to identify new compounds reducing deposition of hyaluronan.
    – To characterize anti fibrotic action of HAS inhibitors.
    – To conduct pilot clinical trial on patients with early stages of liver fibrosis treated with hymecromone (4 methylumbelliferone) (Together with Sechenov Medical University).
    – To establish a panel of LNP RNAi preparations , targeting 12-15 genes, for in vivo studies of liver fibrosis, hepatocellular carcinoma and liver regeneration.
  • Heart failure
    - To investigate effect of itaconate derivatives on modulation of post MI immune response.
    – To investigate the role of hyaluronan mediated processes in post MI scar formation.
  • Duchenne muscular dystrophy
    - Efficacy characterization of therapeutic AAV expressing mini utrohin gene under synthetic promoter in transgenic mouse model mdx mice (in collaboration with Marlin Biotech).
    –  Development of protocol for high scale production of utrophin expressing AAV suitable for phase I clinical studies.
  • Stress related disorders with glucocorticoid overreaction
    - Development of in vivo corticosteroid sensor based on Surface Enhanced Raman Spectroscopy (SERS) in collaboration with PQM CREI.
Mikhail Nesterchuk
Research Scientist
  • Transgenic Models for Drug Discovery
The course consists of theoretical and practic parts.Theoreticla part is devoted to analysis of transgenesis in C.elegance, Drosophila, Zebra fish and mice with particular accent on the usage of these platforms in drug development. It also describes general principles of creation of genetically modified animals. Practical part enables students to obtain practical skills in all phases of the production of transgenic mice.
Transgenic animals are no alternative tool for studying gene function, modeling of human diseases, creating of animal-producing recombinant proteins for agricultural and pharmaceutical industries. Last years work on the creation of such organisms was intensified due to the widespread introduction of site-specific nucleases technology: “zinc fingers», TALEN, CRISPR / Cas9 types of nuclease. Increasingly, it can be heard about the creation of new models of diseases, the use of gene knockout for medical purposes.
The course “Transgenic animals” allows students not only to get acquainted with the theory of molecular biological and embryological basis of modern approaches to the modification of the genome, but also to apply their knowledge during practical training.

ФИО: Котелевцев Юрий Васильевич
Занимаемая должность (должности): Профессор, Заместитель директора ЦНИО
Преподаваемые дисциплины: Генно-модифицированные модели животных в поиске и создании новых лекарств
Ученая степень: кандидат химических наук, 1982, Институт биоорганической химии им. академиков М. М. Шемякина и Ю. А. Овчинникова Российской Академии Наук
Ученое звание: нет
Наименование направления подготовки и/или специальности: химические науки
Данные о повышении квалификации и/или профессиональной переподготовке: нет
Общий стаж работы: 34 года
Стаж работы по специальности: 34 года