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.