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

项目摘要 这项建议的总体目标有两个方面：（1）进行一项创新的研究， 评估母体肥胖对后代转移性小生境重编程的影响，以及（2） 提供一个强大的职业发展和辅导平台，以促进 主要研究者变更为独立研究者。肥胖是一种世界性的流行病， 癌症类型，并与持续性炎症有关。卵巢癌是最致命的妇科疾病 美国女性的癌症5年生存率低（<30%）是由于大多数妇女在诊断时的表现 晚期疾病伴有广泛的腹膜内转移。转移性肿瘤细胞 网膜组织中的脂肪细胞和腹膜腔的间皮衬里。的影响等 母体肥胖对腹膜内转移小生境重编程的影响尚未评估， 实验将检验母体肥胖会导致下一代表观遗传变化的假设。 后代，改变转移小生境，从而影响卵巢癌转移成功。的 拟议的研究计划将利用一个体内模型，包括怀孕的小鼠和它们的幼崽喂养高脂肪 饮食（40%脂肪）相对于对照组（10%脂肪），以表征腹膜内转移瘤的物理变化 微环境以及关键细胞组分的转录组和/或甲基化组的改变。 这些信息将被整合到评估母亲肥胖对卵巢癌影响的研究中 在下一代后代中转移成功。成功完成这些目标将为校长提供 研究者在高级显微镜、转录组学和表观基因组学、生物统计学和 生物信息学和转化的临床前卵巢癌研究。我们召集了一个杰出的 多学科指导团队，并设计了一个具有明确目标的强大职业发展计划 以保证成功。主要研究者的强大背景和职业道德与 专门的指导团队将为我们理解以下方面做出重大而有影响力的贡献： 卵巢癌转移，同时有助于增强科学工作者的多样性。

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.