Genomes and Genes
ADPKD: Understanding mechanisms, Discovering treatments.
Principal Investigator: Xiaogang Li
Affiliation: Stowers Institute for Medical Research
Abstract: DESCRIPTION (provided by applicant): The objective of this proposal is to continue our studies on understanding the mechanisms of tumor necrosis factor-alpha (TNF??) signaling in cystogenesis. TNF?? through its receptor and through the ability of the receptor associated proteins to form the membrane bound pro-survival complex I as well as the cytoplasmic pro-death complex II help cancer cells to escape apoptosis. The inhibitor of apoptosis (IAP) antagonist, Smac-mimetic, is able to target the above TNF??-mediated complexes to induce cancer cell death. Our studies have suggested that TNF?? can promote ADPKD progression and our preliminary studies have further found: 1) TNF?? is always present in cyst fluid from ADPKD kidneys;2) Loss of polycystin function leads to increased expression of TNF?? receptor I (TNFR-I);3) The components of proteins in complex I and complex II are upregulated in Pkd1 mutant MEK cells;4) Most importantly, TNF?? alone could not induce normal or Pkd1 mutant epithelial cell death even at high concentrations, while, TNF?? together with transiently transfected Smac could induce only Pkd1 mutant cystic epithelial cell death but had no effect on Pkd1 wild type kidney epithelial cells. Furthermore, the following evidence supports the connection between TNF?? and Id2 signaling pathways: 1) TNF?? activates mTOR through IKK? and mTOR regulates the functional differentiation of mammary epithelial cells through regulating the expression of Id2;2) Receptor activator of NF-?B ligand (RANKL), a TNF family molecule, regulates mammary epithelial cell proliferation via Id2 by triggering marked nuclear translocation of Id2. Based on these findings, we hypothesize that: TNF?? and its receptor are able to regulate cystic epithelial cell apoptosis through the membrane bound pro-survival complex I and cytoplasmic pro-death complex II and further regulate cystic epithelial cell proliferation and differentiation through mTOR or RANKL-mediated Id2 signaling. To test our hypothesis, we propose three aims: 1) To Investigate the mechanism(s) of TNF?? signaling in regulation of kidney epithelial cell survival;2) To determine the potential role and mechanism of the IAP antagonist, Smac-mimetic, in regulating TNF??-dependent cystic kidney epithelial cell death;3) To investigate whether TNF?? signaling regulates cystic epithelial cell proliferation and differentiation through mTOR and RANKL mediated Id2 signaling. Accomplishing this project will further elucidate the role of the pathways downstream of the polycystins in cystogenesis and will identify key regulatory components that may serve as effective targets to slow disease progression. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to continue our studies on understanding the mechanisms of tumor necrosis factor-alpha (TNF??) signaling in cystogenesis. Our general hypothesis is that TNF?? through its receptor to form a membrane bound pro-survival complex protects the cystic epithelial cell apoptosis and IAP antagonist, Smac-mimetic, can induce TNF?? dependent cystic epithelial cell death to further prevent cyst expansion/formation. Accomplishing this project will further elucidate the role of the pathways downstream of the polycystins in cystogenesis and will identify key regulatory components that may serve as effective targets to slow disease progression. The information from our studies will be likely to open new avenues in the research of ADPKD and establish the foundation for developing effective therapies of the disease.
Funding Period: ----------------2010 - ---------------2015-
more information: NIH RePORT
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Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
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J Clin Invest 123:3084-98. 2013..This newly identified role of SIRT1 signaling in cystic renal epithelial cells provides the opportunity to develop unique therapeutic strategies for ADPKD. ..
- Smac-mimetic-induced epithelial cell death reduces the growth of renal cystsLucy X Fan
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J Am Soc Nephrol 24:2010-22. 2013....
- SIRT2 regulates ciliogenesis and contributes to abnormal centrosome amplification caused by loss of polycystin-1Xia Zhou
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Hum Mol Genet 23:1644-55. 2014..Our results suggest a novel function of SIRT2 in cilia dynamics and centrosome function, and in ciliopathy-associated disease progression. ..
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Department of Pediatrics and Physiology, Medical College of Wisconsin, Milwaukee, WI53226, USA
Biochim Biophys Acta 1812:1213-8. 2011..This article is part of a Special Issue entitled: Polycystic Kidney Disease...
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Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
Kidney Int 81:76-85. 2012..Thus, HDAC inhibition targets Id2-mediated pathways to downregulate cystic epithelial cell proliferation and hence cystogenesis...