The functional connection between human polycystic kidney diseases and cilia is based in part on the overlap between genes whose mutation results in kidney cyst formation and genes whose protein products are expressed in the cilia-basal body complex. The occurrence of a common phenotype, kidney cysts, following mutation in either of these classes of genes has led to a conceptual equation of cellular pathways affected by loss of polycystin-1 (PC1) or polycystin-2 (PC2) with those affected following loss of structurally intact cilia. This proposal is based on our novel observation that cyst formation following inactivation o either Pkd1 or Pkd2 is markedly slowed if structurally intact cilia are concomitantly ablated. This effect is present in adult onset and early developmental mouse models of both Pkd1 and Pkd2 and is independent of the genetic mechanism of cilia ablation. The findings provide genetic evidence for a pathway that is inhibited by the PC1/PC2 complex and that requires intact cilia to produce maximal cyst promoting signals in the absence of PC1/PC2-a Cilia Dependent Cyst Activating (CDCA) pathway. The objective of this proposal are to identify the components of the CDCA pathway. To achieve this objective, we will define the specific determinants of cyst progression whose activity following inactivation of polycystins is modulated by the presence or absence of intact cilia. We will use a highly correlated series of in vivo mouse models that subsume all stages of CDCA to investigate known and novel candidate CDCA pathways. We will complement these directed studies with transcriptomic and proteomic discovery approaches. We have identified integrin signaling as a candidate CDCA activity. We will explore the role of polycystins in integrin signaling in cilia and determine which components of this pathway are active in cilia. We will use gene knockdown in cells and conditional knockout models in mice to determine whether integrin signaling is a component of CDCA and if so, we will target it therapeutically to determine preclinical efficacy in ADPKD. The overall program offers two novel discoveries regarding the pathogenesis of ADPKD that each have substantial potential for translation.

Public Health Relevance

Polycystic kidney disease (PKD) affects 600,000 individuals in the US and is one of the leading causes of end stage kidney failure. Despite this, no specific therapies exist for this disorder. We have found genetic evidence loss of the PKD genes results in activation of a pathway whose function relies on cilia. We seek to identify this novel pathway with the expectation that it will be good target for treatment of PKD. PHS 398/2590 (Rev. 06/09) Page 59 Continuation Format Page

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (KMBD)
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Rasooly, Rebekah S
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Fedeles, Sorin V; Gallagher, Anna-Rachel; Somlo, Stefan (2014) Polycystin-1: a master regulator of intersecting cystic pathways. Trends Mol Med 20:251-60