Cysfic kidney disease (CKD) is proposed to originate from an underlying ciliary defect, though molecular mechanisms remain unclear. We have identified a novel ciliary protein, THM1 (Tetratricopeptide Repeat Containing Hedgehog Modulator 1, also termed TTC21B or IFT139), which negatively regulates Hedgehog (Hh) signaling. Recently, THM1 has been shown to contribute the most pathogenic alleles among ciliary genes to patients with ciliopathies, including Meckel-Gruber Syndrome (MKS), Bardet-Bledl Syndrome (BBS), nephronophthisis (NPHP), Joubert's Syndrome (JS) and Jeune's Asphyxiating Thoracic Disorder (JATD). A major clinical feature of these ciliopathies is CKD, and indeed, genetic deletion of Thml during late embryogenesis results in CKD in the adult mouse. While Hh signaling has not been studied extensively in CKD, our analyses of THM1 have led us to investigate a possible role for enhanced Hh activity in renal cystogenesis. In support of this hypothesis, cyst formation in an embryonic culture model of CKD was prevented by genetic deletion of Gli2, the main transcriptional activator of Hh signaling, and by treatment with small molecule Hh inhibitors. The goal of this proposal is to determine whether enhanced Hh activity leads to renal cysts. In the first aim, the effect of paracrine Hh signaling in CKD will be elucidated by conducting a spatial and temporal quantitative assessment of Hh signaling in the Thm1 conditional knock-out mouse. In the second aim, this spatial analysis will be extended by examining the effects of ablating Thm1 in renal tubular epithelial cells versus in renal stromal cells. In the third aim, causality of increased Hh signaling in renal cystogenesis will be explored by down regulating the Hh pathway genetically and pharmacologically in Thm1 conditional knock-out mice. Examining gene expression in a spatial context may provide a tool with which to gain better understanding of the pathogenesis of CKD. Furthermore, these experiments will establish a causal role for Hh signaling in renal cystogenesis and may offer important implications for the design of preventive strategies against CKD.

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; Cystic kidney disease (CKD) is a leading cause of renal failure, proposed to originate from defective ciliary physiology. This proposal aims to determine whether enhanced Hedgehog (Hh) signaling leads to CKD in a conditional knock-out mouse of Thm1, the most commonly mutated ciliary gene in patients with ciliopathies and a negative regulator of Hh signaling.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Lui, Asona; New, Jacob; Ogony, Joshua et al. (2016) Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells. BMC Cancer 16:487
Briley, Shawn M; Jasti, Susmita; McCracken, Jennifer M et al. (2016) Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction 152:245-60
Navakanitworakul, Raphatphorn; Hung, Wei-Ting; Gunewardena, Sumedha et al. (2016) Characterization and Small RNA Content of Extracellular Vesicles in Follicular Fluid of Developing Bovine Antral Follicles. Sci Rep 6:25486
Wilson, C; Qiu, L; Hong, Y et al. (2016) The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene :
Wang, Huizhen; Hastings, Richard; Miller, William L et al. (2016) Fshb-iCre mice are efficient and specific Cre deleters for the gonadotrope lineage. Mol Cell Endocrinol 419:124-38
Zhang, Zhen; Costa, Flávia C; Tan, Ee Phie et al. (2016) O-Linked N-Acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Interact with Mi2β Protein at the Aγ-Globin Promoter. J Biol Chem 291:15628-40
Belousov, Andrei B; Fontes, Joseph D (2016) Role of neuronal gap junctions in NMDA receptor-mediated excitotoxicity and ischemic neuronal death. Neural Regen Res 11:75-6
Pei, Lei; Solis, Glenn; Nguyen, Mien T X et al. (2016) Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest 126:2509-18
Li, Yuan; McGreal, Steven; Zhao, Jean et al. (2016) A cell-based quantitative high-throughput image screening identified novel autophagy modulators. Pharmacol Res 110:35-49
Wilson, Nathan R; Olm-Shipman, Adam J; Acevedo, Diana S et al. (2016) SPECC1L deficiency results in increased adherens junction stability and reduced cranial neural crest cell delamination. Sci Rep 6:17735

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