Research in Renal Cell Biology and Signaling
Dr. Andrey Sorokin's laboratory 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.
i. Studies are being performed to explore molecular mechanisms responsible for manifestation of short-and long-term effects of Endothelin-1 (ET-1) in kidney cells. ET-1 exerts vasoconstrictor, hypertrophic and mitogenic actions on the renal vasculature and glomerular mesangial cells. In particular, laboratory is interested in 1.) identifying mechanisms involved in regulation or signaling via guanine nucleotide exchange factors Pix and C3G; 2.) evaluation of the role of cytoplasmic tyrosine kinase Pyk2; 3.) elucidation of the negative regulation of endothelin signaling on the level of intracellular MAPK cascades by dual specificity phosphatases.
ii. Studies are being performed to define the role of adaptor proteins Crk and p66 Shc in regulation of distinct intracellular signaling cascades in renal cells. This laboratory has cloned a novel and biologically distinct member of the Crk family that has been termed CrkIII. Adaptor protein p66 Shc controls oxidative stress apoptotic responses and regulates life span in mammals. The ability of p66 Shc to control oxidative cell response apoptosis and animal longevity is unequivocally dependent on Ser phosphorylation of p66 Shc. It is likely that longevity is unequivocally dependent on Ser phosphorylation of p66 Shc. It is likely that signaling via Crk and p66 Shc is extremely important agents and is affected during the progression of kidney disease.
iii. The role of COX-2 in the cell has been the focus of intense investigation since discovery of this enzyme. This 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 casual 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. Apoptosis is important for reparative glomerular remodeling in glomerulonephritis.