The Impact of Maternal Obesity on the Reprogramming of the Metastatic Microenvironment

项目总结

PROJECT SUMMARY The overall objectives of this proposal are two-fold: (1) to conduct an innovative research study that evaluates the impact of maternal obesity on re-programming of the metastatic niche in offspring and (2) to provide a robust career development and mentoring platform to promote the successful transition of the Principal Investigator to an independent investigator. Obesity is a worldwide epidemic that is linked to many cancer types and is associated with persistent inflammation. Ovarian cancer is the most lethal gynecological cancer in U.S. women. Poor 5-year survival rates (<30%) are due to presentation of most women at diagnosis with advanced stage disease with widely disseminated intraperitoneal metastasis. Metastatic tumor cells home to adipocytes in omental tissue and to the mesothelial lining of the peritoneal cavity. As the influence of maternal obesity on reprogramming of the intraperitoneal metastatic niche has not been evaluated, proposed experiments will test the hypothesis that maternal obesity induces epigenetic changes in next generation offspring, modifying the metastatic niche and thereby impacting ovarian cancer metastatic success. The proposed research plan will utilize an in vivo model comprised of pregnant mice and their pups fed a high fat diet (40% fat) relative to controls (10% fat) to characterize physical changes in the intraperitoneal metastatic microenvironment as well as alterations in the transcriptome and/or methylome of key cellular components. This information will be integrated into studies evaluating the impact of maternal obesity on ovarian cancer metastatic success in next generation offspring. Successful completion of these aims will provide the Principal Investigator additional training in advanced microscopy, transcriptomics and epigenomics, biostatistics and bioinformatics, and translational pre-clinical ovarian cancer research. We have assembled an outstanding multi-disciplinary Mentoring Team and designed a robust career development plan with well-defined objectives to guarantee success. The strong background and work ethic of the Principal Investigator in collaboration with the dedicated Mentoring Team will result in significant and impactful contributions to our understanding of ovarian cancer metastasis while simultaneously contributing to enhanced diversity in the scientific workforce.