Hippo Signaling in Polycystic Kidney Disease
Abstract
Polycystic kidney disease (PKD) is a genetic disorder characterized by the formation of multiple fluid-filled cysts, resulting in dramatic enlargement of the kidneys. There are two types of PKDs, the autosomal dominant polycystic kidney disease (ADPKD) and the autosomal recessive polycystic kidney disease (ARPKD), among which the ADPKD represents the most common disease type. Although PKD1 and PKD2 were discovered over 20 years ago as the underlying genes mutated in ADPKD, the molecular function of PKD1 and PKD2 are still poorly understood, which hampers the development of effective therapeutics against this devastating disease. The Hippo pathway is a recently discovered signaling pathway that regulates tissue formation and homeostasis in diverse animals from Drosophila to mammals. This pathway comprises multiple tumor suppressors in a signaling cascade that culminates in the phosphorylation and inactivation of the oncoprotein YAP/TAZ. In our recently completed Peer Reviewed Medical Research Program (PRMRP) award project, we discovered an important role for the Hippo pathway effector YAP/TAZ in regulating kidney cystogenesis downstream of PKD1, and further elucidated a signaling cascade mediating the regulation of YAP/TAZ by PKD1. The functional link between PKD1 and the Hippo pathway offers an unprecedented opportunity to develop molecular targeted therapies against PKD1. Building on these preliminary studies, the overall goal of this PRMRP Expansion Award is to elucidate the precise molecular mechanism by which PKD1 regulates Hippo signaling and to further explore the possibility of genetic and pharmacological inhibition of this signaling cascade as potential therapeutics against PKD. Since a number of proteins in signaling cascade linking PKD1 to YAP/TAZ are currently being pursued by academic labs and pharmaceutical companies as drug targets for cancer therapeutics, the proposed PRMRP project will synergize with the ongoing cancer-focused efforts and expand the usage of these potential cancer drugs to polycystic kidney diseases. In summary, our proposed study represents a new direction for PKD research. If successful, the proposed research will elucidate the molecular pathway underlying PKD1-dependent cystogenesis (short-term impact) and will uncover novel drug targets and candidate drugs for therapeutic intervention of PKD (long-term impact).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010246
Entities
People
- Duojia Pan
Organizations
- United States Army
- University of Texas Southwestern Medical Center