Grant: Operating Grant

Focal segmental glomerulosclerosis, FSGS, is a devastating form of renal disease that begins silently with protein leakage into the urine and progresses inexorably to end-stage kidney failure. FSGS represents the final common response of the kidney to intrinsic (genetic) and extrinsic (environmental toxins) factors that damage renal glomeruli. FSGS is the primary diagnosis in 12% of North American children who require renal transplantation. In renal biopsies, pathologists note widespread smearing of the delicate foot-like projections of kidney cells ("podocytes") that normally prevent passage of protein into the urine. It is this striking disturbance of podocyte cell shape in FSGS that is the subject of our research. We hypothesize that the internal network of fibers providing structural support to podocyte projections is normally organized by a set of proteins collectively called the planar cell polarity (PCP) pathway. PCP molecules organize cell structure patterns in lower species; we have recently shown that disruption of PCP molecules produce human disease such as congenital neural tube defects and disorganization of the inner ear. Our preliminary findings now suggest that the PCP pathway regulates podocyte architecture as well. In this project we will determine whether disruption of the PCP pathway is central to the pathogenesis of FSGS. If so, our research will suggest a completely novel pathway which may be susceptible to therapeutic manipulation in designing new strategies to treat this often incurable condition.