Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited renal failure in the US. Although the disease is named for its most notable feature, namely kidney cysts, vascular complications are in fact a significant cause of morbidity and mortality. Based on the association of aneurysms and ADPKD it has been speculated that polycystins (PKD proteins) play an important role in maintaining vascular integrity of blood vessels but the precise cellular function of polycystins in the vasculature has not been defined. In support of this hypothesis, animals with mutations in either PKD gene die in utero and often exhibit hemorrhage with leaky blood vessels and edema. Despite the significance of this problem, the precise cellular function of polycystins in the vasculature has not yet been defined. We believe that exciting new clues may come from the relationship between PKD and connective tissue diseases such as Marfan syndrome (MFS) that also have a prominent vascular phenotype. Until recently it was assumed that the pathogenic mechanism underlying the MFS phenotype had to do with the structural failure of the ECM. However, recent work suggests that over activity of TGF-beta signaling may play a role in disease pathogenesis. The observation that families with ADPKD and MFS have overlapping clinical features prompted us to test for a functional interaction between 2 gene products. Our preliminary studies demonstrate that mice which are heterozygous for mutations in Pkd1 and the MFS gene, Fbn1, have a remarkable increase in the aortic wall pathology as well as evidence of increased TGF-beta signaling. This application seeks to define the mechanism that is responsible for this genetic interaction. In the first aim we will test the hypothesis that loss of a Pkd1 or Pkd2 allele results in worsening of the histopathologic features of MFS. The goal of Aim 2 is to understand how Fbn1 and Pkd1 cooperatively modulate TGF-beta signaling. We will use a variety of histochemical, cell culture and in vivo methods to interrogate the TGF-beta signaling.
Aim 3 will extend these studies by asking whether Pkd1 affects TGF-beta signaling via STAT-1 dependent induction of the inhibitory SMAD7.
Aim 4 will test the hypothesis that disruption of the Pkd1 alone results in a vascular phenotype and that is associated with the dysregulation of TGF-beta superfamily signaling. We anticipate that an improved understanding of vascular signaling pathways in ADPKD will result in therapeutic approaches that could be applied to the treatment or prevention of some of the most devastating consequences of this disease. We propose the following specific aims:
Specific Aim 1 : Elucidate the pathogenesis of the aortic phenotype in mice carrying compound heterozygous Pkd/Fbn mutations.
Specific Aim 2 : Interrogate the TGF-B signaling pathway in Pkd/Fbn Compound Heterozygotes.
Specific Aim 3 : Test the hypothesis that PKD1 affects TGF-B signaling via STAT-1 dependent induction of the inhibitory SMAD7.
Specific Aim 4 : Test the hypothesis that disruption of Pkd1 is sufficient to modulate TGF-B related signaling pathways. ? ? ?
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