Role of Integrin-Beta 1 in Polycystic Kidney Disease
Annual rept. 1 Apr 2010-31 Mar 2011
MOUNT SINAI SCHOOL OF MEDICINE NEW YORK
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Autosomal Dominant Polycystic Kidney Disease ADPKD is caused by the dysregulation of the PKD1 or PKD2 genes. Among the multiple molecular and biological changes associated with the cystogenic conversion are the amplification of the centrosome, genomic instability and aneuploidy, as well as an increase in the expression of the adhesion molecule integrin1. The scope of the study is to elucidate in the molecular mechanism underlying these events and the role of Int1 in ADPKD pathogenesis. Our recent work has confirmed that Int1 inhibition reverses the centrosome amplification and the increased fibronectin deposition that distinguish cystic as well PC1 knockdown cells. We have also characterized a novel cell line from human loop of Henle epithelium that can serve as a unique model to study medullary cystic kidney disease-2 MCKD2 and familial juvenile hyperuricemic nephropathy FJHN. MCKD2 and FJHN are autosomal dominant diseases with renal cystic involvement that are caused by aberrant function of the ciliary uromodulin gene. Using this model we have observed similar centrosomal amplification and genetic instability upon knockdown of uromodulin, suggesting that these biological changes may be a common denominator of the renal cystic phenotype. Breeding of the mice with floxed Pkd1 and Itgb1 Int1 genes to be crossed with the specific transgenic mouse expressing the Cre recombinase under the control of the kidney-restricted Aqp2 promoter is progressing on schedule.
- Anatomy and Physiology
- Medicine and Medical Research