Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases worldwide. Mutations in the PKD1 or PKD2 genes lead to phenotypic changes in affected renal epithelial cells that include increased proliferation and apoptosis, defects in protein trafficking and changes in transepithelial transport functions. This leads to the formation of large renal cysts, the destruction of the normal renal tissue and finally renal failure. Since the functions of the PKD1/2 gene products, polycystin-1 and polycystin-2, are currently unknown, the rational design of strategies for therapeutic intervention has been difficult. This research proposal seeks to close the gap in our knowledge on what lies between PKD1 gene mutations and the epithelial phenotype that finally leads to cyst formation. We have developed an in vitro cell culture system in the polarized renal epithelial cell line MDCK for the tetracycline-regulated expression of polycystin-1 domains that are proposed to act as dominant-negative inhibitors of the endogenous protein. Preliminary results show that this leads to the induction of several of the typical phenotypes of authentic cystic epithelial cells in ADPKD such as increased proliferation, apoptosis and apical mistargeting of the EGF receptor. The molecular mechanisms that lie downstream of the polycystin-1 defect and are responsible for these phenotypes will be identified and their relationship to each other defined. Proteins that interact with the dominant-negative polycystin-1 domains to mediate these mechanisms will be identified. Of particular importance is the investigation of defects in intracellular membrane trafficking that have been proposed to be responsible for several of the final phenotypes of cystic epithelial cells. Preliminary results from this laboratory suggest that specific changes in the SNARE membrane fusion machinery are involved in membrane trafficking defects ADPKD. The role of these SNARE changes in the acquisition of the cystic epithelial phenotype, and how they are caused by polycystin-1 disruption will be investigated. These studies will help to define the normal function of polycystin-1 and the downstream effects that result from its disruption.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Rasooly, Rebekah S
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University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
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Giovannone, Adrian J; Reales, Elena; Bhattaram, Pallavi et al. (2018) Tracking Endocytosis and Intracellular Trafficking of Epitope-tagged Syntaxin 3 by Antibody Feeding in Live, Polarized MDCK Cells. Bio Protoc 8:
Giovannone, Adrian J; Winterstein, Christine; Bhattaram, Pallavi et al. (2018) Soluble syntaxin 3 functions as a transcriptional regulator. J Biol Chem 293:5478-5491
Giovannone, Adrian J; Reales, Elena; Bhattaram, Pallavi et al. (2017) Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes. Mol Biol Cell 28:2843-2853
Olsan, Erin E; Matsushita, Tamami; Rezaei, Mina et al. (2015) Exploitation of the Polymeric Immunoglobulin Receptor for Antibody Targeting to Renal Cyst Lumens in Polycystic Kidney Disease. J Biol Chem 290:15679-86
Talbot, Jeffrey J; Song, Xuewen; Wang, Xiaofang et al. (2014) The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation. J Am Soc Nephrol 25:1737-48
Weimbs, Thomas; Olsan, Erin E; Talbot, Jeffrey J (2013) Regulation of STATs by polycystin-1 and their role in polycystic kidney disease. JAKSTAT 2:e23650
Weimbs, Thomas; Talbot, Jeffrey J (2013) STAT3 Signaling in Polycystic Kidney Disease. Drug Discov Today Dis Mech 10:e113-e118
Weimbs, Thomas (2011) Third-hit signaling in renal cyst formation. J Am Soc Nephrol 22:793-5
Talbot, Jeffrey J; Shillingford, Jonathan M; Vasanth, Shivakumar et al. (2011) Polycystin-1 regulates STAT activity by a dual mechanism. Proc Natl Acad Sci U S A 108:7985-90
Olsan, Erin E; Mukherjee, Sambuddho; Wulkersdorfer, Beatrix et al. (2011) Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease. Proc Natl Acad Sci U S A 108:18067-72

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