Modulation of PPAR-Gamma Signaling in Prostatic Carcinogenesis
Annual rept. 1 Sep 2008-1 Sep 2009
VANDERBILT UNIV MEDICAL CENTER NASHVILLE TN
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The long term objective of this work is to elucidate metabolic pathways which can be used to reduce the need for radical surgery in patients at high risk for prostate cancer or with early stage disease. The hypothesis to be tested is that alterations to lipoxygenase LOX and cyclooxygenase COX activity in early prostate cancer represent distinct druggable pathways which can be treated in conjunction with the PPAR-gamma signaling pathway to slow or prevent the development and progression of prostate cancer. In the second year of funding, we have generated and applied the various viral vectors PPAR-gamma siRNAs, COX and LOX shRNA and overexpression and have generated many of the tissue recombinants needed to perform the proposed experiments. We have completed the majority of the experiments proposed in specific aim 1 and are writing this work up for publication. As in the mouse model loss of PPAR-gamma function in human epithelium leads to a PIN phenotype which can be promoted to cancer with additional genetic insults. We have generated cells and recombinants with altered COX and LOX expression for the experiments proposed in specific aim 2 which are now ongoing. Work for specific aim 3 is just starting. The second year of work has demonstrated that the combination of PPAR-gamma loss with other common genetic insults can cause progression of a PIN phenotype.
- Medicine and Medical Research