Mechanisms of Fibrillin-Polycystin-1 Interaction

Johns Hopkins University, Baltimore MD

Investigators

Abstract

DESCRIPTION (provided by applicant): Vascular complications are significant causes of morbidity and mortality in ADPKD. Speculation that polycystins play important role in maintaining vessel integrity, but precise cellular function of polycystins in vasculature has not been defined. We believe that exciting new clues may come from relationship between PKD and FBN whose mutation causes Marfan's syndrome that also has a prominent vascular phenotype. Recent work suggests over activity of the TGF-b signaling pathway may play role in Marfan's pathogenesis. A small number of ADPKD families with features similar of Marfan's syndrome suggest these 2 diseases might be related. Preliminary studies demonstrate transheterozygotes increased incidence of severe cardiac defects and abnormalities in organization of aortic wall. This proposal focuses on understanding mechanism for this genetic interaction. In 1st aim we will test that genetic interaction is due to cooperative modulation of TGF-b signaling pathway. We'll use tissues and cells from transheterozygous mice to examine various steps in FGF-b pathway. We'll test that fibrillin may be ligand for extracellular domain of PKD1. In 2nd, we examine overexpression of PKD1 down regulates TGF-b signaling via the STAT-1 dependent induction of SMAD7.