Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Developmental, Regenerative and Stem Cell Biology

Language

English (en)

Date of Award

Spring 4-24-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Indira U Mysorekar

Abstract

The bladder is the site of various diseases such as urinary tract infections: UTI), bladder pain syndrome/interstitial cystitis: BPS/IC), and bladder cancer. UTIs and BPS/IC primarily afflict women and treatment costs over $5 billion and almost $200 million respectively in 2006. Quality of life in BPS/IC patients is low; comparable to individuals with end stage renal disease. Recent research has identified a role for the epithelial lining of the bladder, which is usually targeted by these afflictions, in potentially contributing to enhancing pain. The bladder epithelium also showcases a rapid ability to regenerate after injury.

Knowledge of the contribution of bladder injury to nociception: pain) is currently lacking. To increase our understanding of how various injuries, which target different layers of the bladder, affect pain response in mice we used a UTI injury model from instillation of uropathogenic E. coli: UPEC), a cellular damage model from single dose protamine sulfate: SDPS) instillation, and an inflammatory damage model from multiple instillations of lipopolysaccharide: LPS). We identified that UPEC injury increased the pain response to bladder distention while it was decreased by SDPS injury. LPS injury did not change the pain profile from distention. Secondly, we applied the UPEC infection model to identify that metabotropic glutamate receptor 5: mGluR5) is necessary to experience inflammatory-mediated pain responses. We also correlated molecular markers and pain profiles to identify potential biomarkers for diagnosis or treatment of BPS/IC.

Although regeneration from bladder injury has been studied in the extremes of injury: UPEC and SDPS), many etiologies occur as a spectrum of tissue responses and would be better represented by injury models that showcase nuanced traits. New injury models were developed utilizing dual dose protamine sulfate: DDPS) to specifically target cellular injury to different strata of the bladder epithelial layer. Comparing DDPS to SDPS and UPEC injuries, we identified that extreme urothelial injury alone is sufficient to activate a UPEC-like renewal response originating from the basal most layer. However, DDPS does not require BMP signaling for activation of regeneration. We also identified that the glycosaminoglycan layer of the extracellular matrix is differentially modulated by DDPS injury. In summary, these data suggest that differential injury contributes to pain response and that multiple molecular mediators play a role in regulating bladder epithelial regeneration.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7445JGN

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