? Collapsing glomerulopathy, a clinically aggressive and therapeutically resistant variant of focal segmental glomerulosclerosis, has become a major cause of end-stage renal disease within the last two decades. Collapsing glomerulopathy is associated with disorders that induce strong T helper type 1 (Th1) immune responses, suggesting not only that Th1 effectors play an important role in the pathogenesis of collapsing glomerulopathy, but also that immunomodulation in collapsing glomerulopathy should be investigated. We recently determined in pre-clinical studies that small molecule cyclin-dependent kinase (CDK)/glycogen synthesis kinase-3( (GSK-3() inhibitors may be very effective therapy for collapsing glomerulopathy, however, their immunomodulatory properties, particularly via GSK-3(, a key signaling molecule in CD4+ T lymphocyte activation, are poorly understood. In this study, we propose the following specific aims: 1) to determine in CD4+ mouse lymphocytes whether GSK-3( deletion by inhibitory RNA, GSK-3( inhibition by lithium, or CDK/GSK-3( inhibition by flavopiridol or roscovitine, suppress specific induction or effector responses of Th1-polarizing or Th2-polarizing lymphocytes in vitro; 2) to determine in mice whether flavopiridol or roscovitine suppress specific effector responses of committed Th1 or Th2 splenocytes at efficacious doses for collapsing glomerulopathy in vivo; 3) to determine whether systemic Th1 or Th2 immune deviation retards or accelerates the development of renal disease in the Tg26 HIV-1 transgenic mouse model of collapsing glomerulopathy; and 4) to determine in kidney biopsies from the NIH/NYU Podocyte Disease Registry whether CD4+ Th1 effectors rather than CD4+ Th2 effectors traffic to kidneys with collapsing glomerulopathy when compared to other variants of focal segmental glomerulosclerosis. These studies should elucidate important cell-mediated immune mechanisms in the pathogenesis of collapsing glomerulopathy and delineate the therapeutic specificity of small molecule CDK/GSK-3( inhibitors in the immune deviation of collapsing glomerulopathy-associated disorders ? ?
| Bruggeman, Leslie A; Drawz, Paul E; Kahoud, Nicole et al. (2011) TNFR2 interposes the proliferative and NF-ýýB-mediated inflammatory response by podocytes to TNF-ýý. Lab Invest 91:413-25 |
| Kim, Zae; Nelson, Peter J (2009) Interfacing kidney stroma with dendritic cells. J Am Soc Nephrol 20:685-6 |
| Velázquez, Peter; Dustin, Michael L; Nelson, Peter J (2009) Renal dendritic cells: an update. Nephron Exp Nephrol 111:e67-71 |
| Bruggeman, Leslie A; Nelson, Peter J (2009) Controversies in the pathogenesis of HIV-associated renal diseases. Nat Rev Nephrol 5:574-81 |
| Obligado, S H; Ibraghimov-Beskrovnaya, O; Zuk, A et al. (2008) CDK/GSK-3 inhibitors as therapeutic agents for parenchymal renal diseases. Kidney Int 73:684-90 |
| John, Rohan; Nelson, Peter J (2007) Dendritic cells in the kidney. J Am Soc Nephrol 18:2628-35 |
| Faulhaber, Jason R; Nelson, Peter J (2007) Virus-induced cellular immune mechanisms of injury to the kidney. Clin J Am Soc Nephrol 2 Suppl 1:S2-5 |
| Barisoni, Laura; Nelson, Peter J (2007) Collapsing glomerulopathy: an inflammatory podocytopathy? Curr Opin Nephrol Hypertens 16:192-5 |
| Nelson, Peter J; Shankland, Stuart J (2006) Therapeutics in renal disease: the road ahead for antiproliferative targets. Nephron Exp Nephrol 103:e6-15 |
| Soos, Timothy J; Meijer, Laurent; Nelson, Peter J (2006) CDK/GSK-3 inhibitors as a new approach for the treatment of proliferative renal diseases. Drug News Perspect 19:325-8 |
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