Despite the fact that they are some of the most common structures in biology, the precise molecular and cellular processes that regulate the formation of epithelial tubules are still unknown. Several recent studies have suggested planar cell polarity (PCP) contributes to the development and/or progression of various tubular diseases including polycystic kidney disease. However, it is still not clear how planar cell polariy is established or what effects it has on tubule development. Over the last several years, we have generated and characterized a number of genetic and chemical methods for perturbing and analyzing PCP in the mouse kidney. We have discovered that Wnt signaling is required for planar orientation of cells within the kidney tubular epithelium and that defects in this process are associated with cyst formation. However, we don't know why. We hypothesize that Wnt signaling mediates patterning of the stroma and that stromal signals establish PCP. Further, we hypothesize that oriented cell movement is required to establish and maintain the proper diameter of kidney tubules. In this proposal, we will use a combination of genetic engineering as well as live cell imaging to test these hypotheses as well as determining whether these processes are perturbed in orthologous models of PKD.

Public Health Relevance

Polycystic kidney disease is a devastating disorder that, outside of organ transplant, has no known cures. In this application, we propose to use mouse genetics, organ culture, live cell imaging and small molecule studies to understand more about the cellular causes of the disease. Not only will these studies be helpful in in advancing our understanding of this disease but many of the reagents and techniques developed will have direct applications in PKD therapeutic studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK090127-01A1
Application #
8506522
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Rasooly, Rebekah S
Project Start
2013-04-15
Project End
2017-03-31
Budget Start
2013-04-15
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$330,426
Indirect Cost
$112,926
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Li, Yuwen; Liu, Jiao; Li, Wencheng et al. (2015) p53 Enables metabolic fitness and self-renewal of nephron progenitor cells. Development 142:1228-41
Pan, Xinchao; Schnell, Ulrike; Karner, Courtney M et al. (2015) A Cre-inducible fluorescent reporter for observing apical membrane dynamics. Genesis 53:285-93
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Wang, Shan-Shan; Gu, Yi-Feng; Wolff, Nicholas et al. (2014) Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. Proc Natl Acad Sci U S A 111:16538-43
Das, Amrita; Tanigawa, Shunsuke; Karner, Courtney M et al. (2013) Stromal-epithelial crosstalk regulates kidney progenitor cell differentiation. Nat Cell Biol 15:1035-44
Carroll, Thomas J; Das, Amrita (2013) Defining the signals that constitute the nephron progenitor niche. J Am Soc Nephrol 24:873-6
Castelli, Maddalena; Boca, Manila; Chiaravalli, Marco et al. (2013) Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis. Nat Commun 4:2658
Wang, Xiaolei; Moon, Jesung; Dodge, Michael E et al. (2013) The development of highly potent inhibitors for porcupine. J Med Chem 56:2700-4

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