Lower urinary tract symptoms associated with benign prostatic hyperplasia and prostatitis have a profound impact on quality of life. Urinary tract voiding syndromes that occur in concert with benign prostate disorders are particularly bothersome and, in extreme cases, can be life threatening. The overarching goal of the work proposed here is to define the role of inflammation in benign prostate pathologies, focusing on long-term effects on epithelial cell gene expression, epigenetics, and differentiation. The rationale for undertaking this study is that we hypothesize that the enduring effects of inflammatory events on prostate growth and differentiation are mediated by epigenetic changes in the epithelium, and the epigenome is currently an accessible drug target. Thus, confirmation of this hypothesis by successful completion of the work proposed here would be rapidly translated into patient benefits by informing new therapeutic applications of existing drugs. Evidence from clinical studies strongly implicates aberrant expression of cytokines in etiology of benign prostatic disease. Cytokines are well known to be primary mediators of the inflammatory response but can also have direct effects on epithelial and stromal cells. To determine the consequences of increased proinflammatory cytokine expression in the prostate, a conditional transgenic mouse model will be developed and characterized. The effects of up-regulated ILI 7 and ILI p on prostate inflammation, morphology, gene expression, and epigenetic marks will be analyzed. The extent of pelvic pain coincident with prostate inflammation in the mouse model will also be ascertained. In parallel, human patient material from open prostatectomy and radical prostatectomy cases with inflammation will be characterized. Patterns of gene expression and DNA methylation in reactive and normal epithelia will be quantified in samples from patients with and without lower urinary tract symptoms. These analyses will provide new insights into the effects of inflammation on the transcriptome and eipgenome of human prostate epithelial cells, which can be capitalized upon both diagnostically and therapeutically in future studies to alleviate the morbidity associated with benign prostatic disease and its coincident voiding syndromes.
The proposed work is directly relevant to human health because it will define changes in cells that occur in prostate diseases. There are existing classes of drugs that may be effective in counteracting these changes, and may therefore be effective in relieving lower urinary street symptoms that commonly occur in benign prostatic hyperplasia and prostatitis patients.
| Shinohara, Debika Biswal; Vaghasia, Ajay M; Yu, Shu-Han et al. (2013) A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes. Prostate 73:1007-15 |
| Rao, Varsha; Heard, Jamie C; Ghaffari, Helya et al. (2012) A Hoxb13-driven reverse tetracycline transactivator system for conditional gene expression in the prostate. Prostate 72:1045-51 |
