This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The ovarian surface epithelium (OSE) is the source of most ovarian cancers in women, yet comprises less than 1/1,000th of the ovary. The basis for OSE transformation is poorly understood, hindering the development of improved strategies for treatment. Since the prognosis for ovarian cancer declines dramatically when the disease is diagnosed at later stages (95% cure rate at stage I, but a 5-year survival rate of only 10% at stage IV), strategies for prevention and early detection may offer the best hope of reducing the number of fatalities from ovarian cancer. We are developing two novel strategies for ovarian cancer prevention: first, we seek to eliminate the OSE completely, using detergent and mild abrasion (epitheliectomy);second, we wish to modulate FANCD2 expression in the OSE. This project more broadly seeks to establish a research program whereby microarray and molecular analysis of OSE cells from healthy, at risk, and cancer patients will identify key elements in OSE transformation. The nonhuman primate system will be used to evaluate these elements as candidates for therapeutic manipulation, and the data will be translated into clinical application for ovarian cancer prevention and early detection therapies. Current data indicate the OSE may be effectively removed without impairing ovarian function. In addition, we have eliminated FANCD2 gene methylation and histone acetylation as probable mechanisms for its downregulation in at-risk women. Ongoing research will determine whether miRNA's are affecting FANCD2 mRNA levels.
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