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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Wang, Huizhen; Luo, Jinping; Carlton, Carol et al. (2017) Sperm-oocyte contact induces outside-in signaling via PYK2 activation. Dev Biol 428:52-62
Padró, Mercè; Louie, Raymond J; Lananna, Brian V et al. (2017) Genome-independent hypoxic repression of estrogen receptor alpha in breast cancer cells. BMC Cancer 17:203
New, Jacob; Arnold, Levi; Ananth, Megha et al. (2017) Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target. Cancer Res 77:6679-6691
Rogers, Robert S; Tungtur, Sudheer; Tanaka, Tomohiro et al. (2017) Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice. Front Neurosci 11:473
Lui, Asona J; Geanes, Eric S; Ogony, Joshua et al. (2017) IFITM1 suppression blocks proliferation and invasion of aromatase inhibitor-resistant breast cancer in vivo by JAK/STAT-mediated induction of p21. Cancer Lett 399:29-43
Tan, Ee Phie; Duncan, Francesca E; Slawson, Chad (2017) The sweet side of the cell cycle. Biochem Soc Trans 45:313-322
Wilson, C; Qiu, L; Hong, Y et al. (2017) The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene 36:2565-2576
Chen, Lei; Zhao, Lin; Samanta, Anweshan et al. (2017) STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPK?/mTOR axis. PLoS One 12:e0179835
Jasti, Susmita; Farahbakhsh, Mina; Nguyen, Sean et al. (2017) Immune response to a model shared placenta/tumor-associated antigen reduces cancer risk in parous mice. Biol Reprod 96:134-144
Samanta, Saheli; Rajasingh, Sheeja; Cao, Thuy et al. (2017) Epigenetic dysfunctional diseases and therapy for infection and inflammation. Biochim Biophys Acta 1863:518-528

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