Understanding how the urothelium grows and differentiates is central to understanding a number of bladder diseases. Being able to modulate these processes would allow us to improve how we repair urinary tract abnormalities in children. Preliminary evidence in our laboratory suggests that Secreted Protein Acidic and Rich in Cysteine (SPARC) plays an important role in regulating DNA synthesis and shape change of urothelial cells, which are two crucial processes involved in control of growth and differentiation of the urothelium. Other processes include a complex network of crosstalk communication between the urothelium and the mesenchyme. We propose to attack the SPARC part of this process because a) nothing is known about the biology of SPARC in the bladder and b) an understanding of how SPARC works in conjunction with these other processes will allow us to develop new and innovative methods to strengthen our translational approach to the problem of bladder and urinary tract disease. In order to achieve these goals, we have established specific aims for this period of support to better understand how SPARC functions in the context of a dynamic steady-state interrelationship that suppresses the progression of the urothelial cell cycle and mediates the attachment of urothelial cells to its underlying basement membrane. A dual role for SPARC in regulating these process is hypothesized to depend on whether SPARC is secreted or whether it remains inside the cell or nucleus. We propose that abundant levels of intracellular SPARC define the normal urothlelial phenotype - that of quiescence. During the proliferative phase, SPARC is no longer sequestered within cells, but instead is secreted into the extracellular space where it contributes to changes in cell shape that accompany the dismantling of focal adhesions, spreading, and a formation of the invasive phenotype. Information gained from this research will provide us with a basic descriptive understanding of SPARC function that we will use to design SPARC implants that will be tested clinically or in animal models by which SPARC modulates urothelial function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK058881-01A2
Application #
6477718
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Mullins, Christopher V
Project Start
2002-04-10
Project End
2007-03-31
Budget Start
2002-04-10
Budget End
2003-03-31
Support Year
1
Fiscal Year
2002
Total Cost
$246,907
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
Zhang, Hongyong; Aina, Olulanu H; Lam, Kit S et al. (2012) Identification of a bladder cancer-specific ligand using a combinatorial chemistry approach. Urol Oncol 30:635-45
Zhang, Dianzhong; Hudson, Amber E; Delostrinos, Catherine F et al. (2011) Dual sources of vitronectin in the human lower urinary tract: synthesis by urothelium vs. extravasation from the bloodstream. Am J Physiol Renal Physiol 300:F475-87
Hudson, Amber E; Carmean, Nicole; Bassuk, James A (2007) Extracellular matrix protein coatings for facilitation of urothelial cell attachment. Tissue Eng 13:2219-25
Kosman, Jeffrey; Carmean, Nicole; Leaf, Elizabeth M et al. (2007) The motif of SPARC that inhibits DNA synthesis is not a nuclear localization signal. J Mol Biol 371:883-901
Carmean, N; Kosman, J W; Leaf, E M et al. (2007) Immortalization of human urothelial cells by human papillomavirus type 16 E6 and E7 genes in a defined serum-free system. Cell Prolif 40:166-84
Delostrinos, Catherine F; Hudson, Amber E; Feng, Waldo C et al. (2006) The C-terminal Ca2+-binding domain of SPARC confers anti-spreading activity to human urothelial cells. J Cell Physiol 206:211-20
Hudson, Amber E; Feng, Waldo C; Delostrinos, Catherine F et al. (2005) Spreading of embryologically distinct urothelial cells is inhibited by SPARC. J Cell Physiol 202:453-63