Interstitial cystitis (IC)/painful bladder syndrome (PBS) is a debilitating chronic urologic condition. Over 3 million women above the age of 18 in the U.S. suffer from unrelenting pelvic pain, significant urinary symptoms, recurring urinary infection, bladder fibrosis, and renal failure. In 2007, the cost and disease burden associated with IC/PBS was analyzed by the Urologic Diseases in America Project and found to exceed $750 million annually. We have developed a mouse model of inflammatory cystitis utilizing LL-37, a natural anti-microbial peptide produced in the genitourinary system. Our model recapitulates key aspects of IC/PBS including the induction of profound bladder inflammation, production of bladder-specific pain, urothelial cell injury, glycosaminoglycan (GAG) layer dysfunction, and accumulation of mast cells. To further establish the physiologic relevance of LL- 37 induced cystitis, our group has shown that human urinary LL-37 levels were significantly elevated in pediatric spina bifida patients. In addition within our mouse model, we've demonstrated LL-37 could elicit profound dose dependent bladder inflammation involving the urothelium. Furthermore, the propagation of inflammation involves mast cells in a dose dependent fashion. Mast cells have been well described to be a central cell type mediating pain in patients with IC/PBS. The exact role of mast cell mediated bladder pain in LL-37 induced cystitis remains unclear and will be further investigated in the proposed research. We hypothesize that LL-37 induced cystitis pain intimately involves mast cells. This hypothesis will be tested in Specific Aim 1, by elucidating mast cells as a key effector cell type utilizing our surrogate model. From a therapeutic standpoint, our group has developed novel patented compounds known as semi-synthetic glycosaminoglycan ethers (SAGEs) that attenuates the inflammatory effects of LL-37 by direct immune modulation and interference with mast cell activation. Our preliminary data suggests treatment with SAGE compounds truncates both inflammation and pain observed in LL-37 induced cystitis. The exact mechanism behind how our SAGEs inhibit mast cell derived bladder pain remains unclear and will be further investigated in the proposed research. We hypothesize that mast cell mediated cystitis pain can be attenuated with SAGE compounds. This hypothesis will be tested in Specific Aim 2, investigate SAGE attenuation of mast cell mediated bladder pain. This integrated proposal is innovative with high impact because it will further define mast cell driven cystitis pain and provide detailed knowledge about the pain attenuation properties of our SAGE compounds. These data also provide significant opportunity with a high likelihood of success to further develop novel SAGE compounds as potential pharmaceutical interventions to attenuate not only inflammation associated with IC/PBS but inhibit mast cell mediated bladder pain.

Public Health Relevance

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating chronic condition affecting primarily women. Over 3 million women above the age of 18 in the U.S. suffer from significant lower urinary tract symptoms. This integrated proposal will further define mast cell driven cystitis pain and provide knowledge about the pain attenuation properties of semi-synthetic glycosaminoglycan ether (SAGE) compounds. Ultimately, these data will provide significant opportunity to further develop SAGE compounds as pharmaceutical agents to help the millions of patients afflicted with IC/PBS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK100868-01
Application #
8626142
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (O2))
Program Officer
Kirkali, Ziya
Project Start
2013-09-27
Project End
2014-09-26
Budget Start
2013-09-27
Budget End
2014-09-26
Support Year
1
Fiscal Year
2013
Total Cost
$381,798
Indirect Cost
$125,558
Name
University of Utah
Department
Surgery
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112