Regulation of tumor growth and metabolism by hyperinsulinemia

项目摘要 这份K99/R00提案中的学习和职业发展/培训活动旨在使PI具备以下技能： 雷切尔·佩里博士，拥有技术和科学专业知识以及成为一名独立的 探索肿瘤新陈代谢话题的调查者。为此，佩里博士将在体内进行开发和优化， 体外、体外磁共振和质谱学方法模拟糖酵解和氧化 小鼠结肠癌和肝细胞癌模型以及肿瘤浸润性T细胞的代谢。这些 研究的目的是为了确定高胰岛素血症的机制(S)--它有 已被确定为结肠癌风险和进展的强大贡献者-可能会推动肿瘤的生长。老鼠 结肠癌的肿瘤将用一种新的治疗剂进行治疗，一种控释剂 线粒体原载体(CRMP)逆转高胰岛素血症及其对肿瘤进展和预后的影响 将确定代谢通量速率，将改变的底物氧化速率和/或胰岛素信号关联起来 肿瘤生长过程中的标记物。然后我们将治疗患有非酒精性脂肪性肝炎(NASH)的小鼠- 与CRMP相关的肝细胞癌。因为我们最近证明了这个特工 逆转NASH纤维化，这些实验将检验逆转NASH将减缓肿瘤的假设 CRMP可能是减缓肝癌进展的一个有吸引力的治疗选择。我们还将评估 与正常肝脏相比，肝细胞癌小鼠肝脏中可能发生的代谢通量的变化 使用体内和体外核磁共振/质谱学技术，以及CRMP对这些通量的影响。 因为某些癌症与胰岛素抵抗/高胰岛素血症、非酒精性脂肪 肝病和NASH，当前肥胖的流行需要努力理解其机制(S) 这些因素可能与癌症的发病机制有关，建议的研究有明确的翻译 关联性。 上述工作将由佩里博士在#年的内科/科进行 耶鲁大学医学院内分泌学，在她的导师Gerald博士的指导下 舒尔曼，共同导师苏珊·凯奇博士，以及合作者道格拉斯·罗斯曼博士和迈克尔·波拉克博士。这个 这里的研究是精心设计的，以扩大佩里博士的技术技能，同时磨练她 科学推理并提供职业发展培训，使她能够成为助理教授 在K99阶段结束时(在K99/R00奖项的第二年之后)，并申请独立的R01拨款 R00阶段结束(K99/R00奖项的第5年)。这些目标将通过佩里博士的 在本申请中描述的计划，以进行研究；经常与她的导师、合作者、 以及耶鲁大学教职员工中与这些研究相关的研究兴趣或技术技能的其他成员； 完成课程作业；参加科学会议。

Project Summary The studies and career development/training activities in this K99/R00 proposal are designed to equip the PI, Dr. Rachel Perry, with the technical and scientific expertise and the experience to become an independent investigator exploring the topic of tumor metabolism. To that end, Dr. Perry will develop and optimize in vivo, ex vivo, and in vitro magnetic resonance and mass spectrometry methods to model glycolytic and oxidative metabolism in mouse models of colon and hepatocellular cancer, as well as in tumor-infiltrating T cells. These studies are designed to allow the identification of the mechanism(s) by which hyperinsulinemia – which has been identified as a strong contributor to colon cancer risk and progression – may drive tumor growth. Mice with colon carcinoma tumors will then be treated with a novel therapeutic agent, a controlled-release mitochondrial protonophore (CRMP), to reverse hyperinsulinemia, and its effect on tumor progression and metabolic flux rates will be identified, correlating altered substrate oxidation rates and/or insulin signaling markers in tumors with tumor growth. We will then treat mice with non-alcoholic steatohepatitis (NASH)- associated hepatocellular carcinoma (HCC) with CRMP. Because we have recently shown that this agent reverses NASH fibrosis, these experiments will test the hypotheses that reversing NASH will slow tumor growth, and that CRMP may be an attractive therapeutic option to slow HCC progression. We will also assess the alterations in metabolic flux rates that may occur in livers of mice with HCC as compared to normal livers using in vivo and ex vivo NMR/mass spectrometry techniques, and the effect that CRMP has on those fluxes. Because certain cancers have been associated with insulin resistance/hyperinsulinemia, non-alcoholic fatty liver disease, and NASH, the current obesity epidemic demands efforts to understand the mechanism(s) by which these factors may contribute to cancer pathogenesis, and the proposed studies have clear translational relevance. The work described above will be carried out by Dr. Perry in the Department of Internal Medicine/Section of Endocrinology at the Yale University School of Medicine, under the supervision of her mentor, Dr. Gerald Shulman, co-mentor Dr. Susan Kaech, and collaborators Drs. Douglas Rothman and Michael Pollak. The studies herein are carefully designed to broaden Dr. Perry's arsenal of technical skills as well as hone her scientific reasoning and provide career development training to enable her to become an Assistant Professor at the end of the K99 phase (after year 2 of the K99/R00 award), and to apply for independent R01 funding at the end of the R00 phase (in year 5 of the K99/R00 award). These goals will be achieved through Dr. Perry's plans, described in this application, to perform research; to meet frequently with her mentors, collaborators, and other members of the Yale faculty with research interests or technical skills relevant to these studies; to complete coursework; and to attend scientific meetings.