Associate Provost for Research Boston University Medical Campus
NIDDK - National Institute of Diabetes & Digestive & Kidney Diseases	Research Resources

Abstract

Abstract: DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of end-stage renal disease. Loss of the polycystin-1 - polycystin-2 interaction is central to disease pathogenesis, but the precise mechanism of cyst formation remains unclear. Intriguingly, disordered renal tubule cell proliferation and apoptosis are consistent features of all the cystic renal diseases. Our laboratory has been closely studying the molecular basis of von HippeI-Lindau (VHL) renal disease, which includes a polycystic kidney phenotype. The similarities between the cystogenic pathways in VHL disease and ADPKD are striking. Jade-1 (gene for Apoptosis and Differentiation in Epithelia) encodes a short-lived, highly-regulated pro-apoptotic transcription factor that is stabilized by the VHL tumor suppressor. Jade-1 resides in prominent nuclear speckles and is most highly expressed in renal tubular epithelial cells. Intriguingly, the pattern of naturally occurring VHL mutations that stabilize Jade-1 suggest a correlation with VHL renal disease risk, which has not been previously described. Jade-1 protein alters the monolayer morphology of renal cells and promotes apoptosis that is blocked by VHL. Jade-1 may help propel a pre-apoptotic epithelial cell off a monolayer, promoting anoikis. Remarkably, wild-type polycystin-1 strongly regulates Jade-1 much like VHL, and this effect is blocked by a disease-causing polycystin-1 mutation in the coiled-coil domain that prevents interaction with polycystin-2. Moreover, Jade-1 is the target of a novel polycystin-1 dominant-negative mechanism. Thus, pro-apoptotic Jade-1 is downstream of both VHL and a common polycystin-1 / polycystin-2 regulatory pathway. Jade-1 may therefore be a central regulator of renal cyst formation in VHL disease and ADPKD, and perhaps in other cystic renal diseases. The Jade-1 - polycystin relationship in cystic disease will be explored through the following Aims: AIM 1: The mechanism of Jade-1 regulation by polycystin-1 AIM 2:Jade-1 effects on the cell cycle and modulation by polycystin-1 AIM 3: Direct role of Jade-1 in renal cyst formation.

Thesaurus Terms:
Von Hippel Lindau syndrome, genetic regulation, polycystic kidney, protein structure function
apoptosis, cell cycle, cell differentiation, cytogenetics, urinary bladder epithelium
MDCK cell, clinical research, genetically modified animal, human tissue, immunofluorescence technique, laboratory mouse, laboratory rat, polymerase chain reaction, western blotting

Institution:	BOSTON MEDICAL CENTER
	ONE BOSTON MEDICAL CENTER PLACE
	BOSTON, MA 02118
Fiscal Year:	2006
Department:
Project Start:	01-APR-2004
Project End:	31-MAR-2009
ICD:	NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
IRG:	PTHA