Andrey Sorokin, PhD

Andrey Sorokin, PhD

Professor of Medicine

Dr. Sorokin's research is focused on mechanisms of initiation and progression of proliferative kidney diseases. Research in his laboratory is primarily focused on 1) understanding the role of endothelin signaling in hypertension induced nephropathy and proliferative glomerulonephritis; 2) cellular regulation of prostaglandin production with an emphasis on regulation of Cox-2 activity on the level of catalysis by proteins spatially co-localized with the enzyme in its natural environment; 3) elucidation of BK virus entry pathways and prevention of polyomavirus nephropathy after renal transplantation.

Degrees
MS - St. Petersburg State University, Russia, 1977
PhD - Institute of Cytology Academy of Sciences of Russia, 1981

Postdoctoral
Cell Biology - Institute of Cytology Academy of Sciences of the Russia, 1980-1985


Research in Renal Cell Biology and Signaling
The laboratory of Andrey Sorokin, PhD, is interested in multiple projects with focus on cell signaling as related to pathobiology of kidney disease.

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 mesangial 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 mesangial 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.

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