Immune mechanisms in collapsing glomerulopathy

New York University School Of Medicine, New York NY

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] 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 [unreadable] [unreadable]