Andrey Sorokin, PhD
Professor, Medicine (Nephrology) and Microbiology & Immunology
MS, St. Petersburg State University, Russia, 1977
Postdoctoral, Institute of Cytology Academy of Sciences of Russia, 1985
My research is primarily focused on characterizing the molecular mechanisms underlying the activation and termination of signaling pathways, as well as defining the cellular consequences of specific stimulation of these cascades in systems relevant for the signaling from G-protein coupled receptors. In renal mesangium endothelin-1 (ET-1) exerts excessive contraction, proliferation and extracellular matrix accumulation leading to glomerulosclerosis and kidney failure. We are studying ET-1 –induced signaling cascades underlying proliferation-associated and oxidative stress related renal glomerular diseases. We also investigate the posttranslational regulation of Cyclooxygenase-2 (COX-2), the key inducible enzyme in the production of prostaglandins. Our lab has demonstrated the anti-apoptotic effect of COX-2 in a number of cell systems and provided evidence that COX-2 promotes cell survival by a mechanism linking increased expression of pro-survival genes coupled to inhibition of NO- and superoxide-mediated apoptosis. The significance of ongoing studies is that new knowledge of mechanisms of posttranslational regulation of COX-2 activity will open novel strategies to inhibit COX-2 activity and combat glomerular renal diseases.
Another direction of my research is studying molecular mechanisms of infection of renal cells by BK virus (BKV), a non-enveloped double-stranded DNA polyomavirus. In recent years, nephritis induced by BKV has become a severe problem after renal transplantation. An objective of our studies is to identify the protein component of the BKV receptor and to develop pharmaceutical agents capable of mitigating BKV entry into human renal proximal tubular epithelial cells, considered to be one of the main natural targets of BKV.
Research in Renal Cell Biology and Signaling
Research is primarily focused on characterizing the molecular mechanisms underlying the activation and termination of signaling pathways, as well as defining the cellular consequences of specific stimulation of these cascades in systems relevant for the signaling from G-protein coupled receptors.
By combining of molecular biological, biochemical and cellular biological approaches the defining the alterations in signal transduction which lead to pathological phenotype can be obtained.
In renal mesangium endothelin-1 (ET-1) exerts excessive contraction, proliferation and extracellular matrix accumulation leading to glomerulosclerosis and kidney failure. The molecular mechanisms of ET-1 actions in renal mesangium are insufficiently studied. We aim to prove that novel ET-1 mediated signaling pathways, discovered by us in cultured glomerular messangial cells (GMC), play principal role in glomerular diseases in vivo when ET-1 production is increased and renal mesangium is dysfunctional. To achieve these goals we have generated unique rat strains in which we precisely modified rat genome using engineered Zinc Finger Nucleases (ZFNs) in combination with innovative in vivo knock-in strategy. Until recently the precise modification of rat genome was not possible, but the generation of targeted gene changes using ZFNs in inbred rat strains has become one of the major breakthroughs in the field dramatically increasing opportunities of investigators in utilizing rats for biomedical research. In our studies we have discovered novel signaling pathway stimulated by ET-1 in GMC which involves the formation of multiunit signaling complex including adaptor protein p66 Shc. We are testing hypothesis that ET-1 signaling via adaptor protein p66 Shc in renal mesangium in vivo is contributing to kidney pathologies associated with abnormal function of renal messangial cells. Studies are underway to prove that ET-1-mediated signaling via p66 Shc contributes to renal injury in glomerular diseases associated with enhanced ET-1 production and abnormal glomerular function. We are inducing anti-Thy-1.1 nephritis and hypertension-induced nephropathy in rats which either lack p66 Shc protein or express endogenous p66 Shc with introduced mutations. We also use primary GMC derived from wild type and genetically modified rat strains to uncover the molecular mechanism of p66 Shc signaling in renal mesangium. These studies are important because abnormal GMC function is detected in the majority of patients with hypertension induced nephropathy and glomerulosclerosis. The elucidation of mechanisms of ET-1-induced renal pathologies will result in understanding of the mechanisms underlying proliferation-associated and oxidative stress related renal glomerular diseases.
Cyclooxygenases are key enzymes in the production of prostaglandins and there are multiple studies which emphasize the significance of cyclooxygenase-2 (Cox-2) activity for the progression of renal diseases and particularly glomerular pathologies. Our lab has demonstrated the anti-apoptotic effect of COX-2 in a number of cell systems and provided evidence that COX-2 promotes cell survival by a mechanism linking increased expression of pro-survival genes coupled to inhibition of NO- and superoxide-mediated apoptosis. We have also proved the existence of a causal link between COX-2 and P-gp (MDR1) activity, which would have implications for kidney function and multidrug resistance in tumors where COX-2 is over expressed. Selective Cox-2 inhibitors have been developed but severe side effects limit their clinical implementation. We hypothesize that Cox-2 activity is regulated on the level of catalysis by specific proteins spatially co-localized with the enzyme in its natural environment. We have identified a number of signaling proteins, including adaptor protein Engulfment and cell motility 1 (Elmo1) and tyrosine kinase Fyn, as candidates for the posttranslational regulation of Cox-2 activity. We are testing the hypothesis that cellular regulation of prostaglandin synthesis by Cox-2 in glomerular pathologies occurs by Cox-2 interaction with proteins Elmo1 and Fyn spatially co-localized with Cox-2. Using multi-stage fragmentation mass spectrometry analysis we have identified the exact site of phosphorylation on Cox-2 by Fyn. We have generated Cox-2 mutants with phosphorylation site mutated. We are studying the role of Fyn and Fyn-mediated Cox-2 phosphorylation in ECM-depositing renal glomerular diseases using genetically modified rats deficient in Fyn. The significance of ongoing studies is that this new knowledge will open novel strategies to inhibit Cox-2 activity and combat glomerular renal diseases.
(Miller B, Regner K, Sorokin A.) Biochemical and Biophysical Research Communications. 7 May 2022;603:69-74 SCOPUS ID: 2-s2.0-85125835040 05/07/2022
(Miller B, Regner K, Sorokin A.) Biochem Biophys Res Commun. 2022 May 07;603:69-74 PMID: 35278882 PMCID: PMC8969123 SCOPUS ID: 2-s2.0-85125835040 03/13/2022
(Hughes WE, Hockenberry J, Miller B, Sorokin A, Beyer AM.) Am J Physiol Heart Circ Physiol. 2021 Dec 01;321(6):H1096-H1102 PMID: 34714691 PMCID: PMC8834231 SCOPUS ID: 2-s2.0-85120604529 10/30/2021
(Miller B, Palygin O, El-Meanawy A, Mattson DL, Geurts AM, Staruschenko A, Sorokin A.) Life Sci. 2021 Aug 15;279:119661 PMID: 34087282 PMCID: PMC8265215 SCOPUS ID: 2-s2.0-85107260373 06/05/2021
(Miller B, Kostrominova TY, Geurts AM, Sorokin A.) Int J Mol Sci. 2021 May 15;22(10) PMID: 34063460 PMCID: PMC8155973 SCOPUS ID: 2-s2.0-85105734035 06/03/2021
(Miller B, Kostrominova TY, Geurts AM, Sorokin A.) International Journal of Molecular Sciences. 2 May 2021;22(10) SCOPUS ID: 2-s2.0-85105734035 05/02/2021
(Wright KD, Miller BS, El-Meanawy S, Tsaih SW, Banerjee A, Geurts AM, Sheinin Y, Sun Y, Kalyanaraman B, Rui H, Flister MJ, Sorokin A.) Breast Cancer Res. 2019 Jun 15;21(1):74 PMID: 31202267 PMCID: PMC6570928 SCOPUS ID: 2-s2.0-85067234098 06/17/2019
(Palygin O, Miller BS, Nishijima Y, Zhang DX, Staruschenko A, Sorokin A.) FASEB J. 2019 Feb;33(2):2636-2645 PMID: 30303741 PMCID: PMC6338658 SCOPUS ID: 2-s2.0-85061064863 10/12/2018
(Miller BS, Blumenthal SR, Shalygin A, Wright KD, Staruschenko A, Imig JD, Sorokin A.) Diabetes. 2018 Nov;67(11):2206-2212 PMID: 30131395 PMCID: PMC6198347 SCOPUS ID: 2-s2.0-85055169170 08/23/2018
(Wright KD, Staruschenko A, Sorokin A.) Am J Physiol Renal Physiol. 2018 Feb 01;314(2):F143-F153 PMID: 28978535 PMCID: PMC5866456 SCOPUS ID: 2-s2.0-85043593186 10/06/2017
(Alexanian A, Sorokin A.) Physiol Genomics. 2017 Nov 01;49(11):667-681 PMID: 28939645 PMCID: PMC5792139 SCOPUS ID: 2-s2.0-85044391314 09/25/2017
(Beyer AM, Zinkevich N, Miller B, Liu Y, Wittenburg AL, Mitchell M, Galdieri R, Sorokin A, Gutterman DD.) Basic Res Cardiol. 2017 Jan;112(1):5 PMID: 27995364 PMCID: PMC6758541 SCOPUS ID: 2-s2.0-85006456806 12/21/2016