Regulation of tumor growth and metabolism by hyperinsulinemia

高胰岛素血症调节肿瘤生长和代谢

• 批准号: 9295517
• 负责人: Rachel Jamison Perry
• 金额: $ 14.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295517
• 关键词: Acetates; Acute; Affect; Attention; Award; Cancer Model; Cell Respiration; Cells; Cellular Metabolic Process; Chronic; Colon; Colon Carcinoma; Colonic Neoplasms; Data; Deoxyglucose; Diabetes Mellitus; Diet; Endocrinology; Epidemic; Exhibits; Faculty; Fatty acid glycerol esters; Fibrosis; Functional disorder; Funding; Glucose; Goals; Growth; Health; Hepatic; Hyperinsulinism; In Vitro; Incidence; Inflammation; Infusion procedures; Insulin; Insulin Resistance; Internal Medicine; Intervention; Liver; Magnetic Resonance; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mentors; Metabolic; Methods; Mitochondria; Modeling; Mus; Normal Cell; Obesity; Pathogenesis; Pharmacology; Phase; Plasma; Primary carcinoma of the liver cells; Radioisotopes; Rattus; Regulation; Research; Research Personnel; Role; Skeletal Muscle; Supervision; T-Lymphocyte; Technical Expertise; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tracer; Training; Training Activity; Universities; Work; cancer risk; cancer type; career development; controlled release; design; experience; experimental study; fat burning; glucose metabolism; in vivo; insulin signaling; interest; lipid metabolism; liver inflammation; medical schools; meetings; melanoma; member; mouse model; neoplastic cell; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel therapeutics; outcome forecast; oxidation; professor; stable isotope; tumor; tumor growth; tumor metabolism; tumor progression

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.

项目摘要 本K99/R 00建议书中的研究和职业发展/培训活动旨在使PI， 博士雷切尔·佩里（Rachel Perry），拥有技术和科学专业知识以及成为独立人士的经验 研究者探索肿瘤代谢的主题。为此，佩里博士将在体内开发和优化， 离体和体外磁共振和质谱方法来模拟糖酵解和氧化 在结肠癌和肝细胞癌的小鼠模型中，以及在肿瘤浸润性T细胞中的代谢。这些 研究旨在确定高胰岛素血症的机制， 被认为是结肠癌风险和进展的重要因素-可能会推动肿瘤生长。小鼠 结肠癌的肿瘤将用一种新的治疗剂， 线粒体质子载体（CRMP），逆转高胰岛素血症，及其对肿瘤进展和 代谢通量率将被确定，与改变的底物氧化率和/或胰岛素信号传导相关 肿瘤生长的肿瘤标志物。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（HCC）。因为我们最近的研究表明 逆转NASH纤维化，这些实验将测试逆转NASH将减缓肿瘤生长的假设。 CRMP可能是减缓HCC进展的有吸引力的治疗选择。我们亦会评估 与正常肝脏相比，HCC小鼠肝脏中可能发生的代谢通量率的改变 使用体内和体外NMR/质谱技术，以及CRMP对这些通量的影响。 由于某些癌症与胰岛素抵抗/高胰岛素血症有关，因此非酒精性脂肪性癌症可能与胰岛素抵抗/高胰岛素血症有关。 肝脏疾病和NASH，目前的肥胖流行病需要努力了解机制， 这些因素可能有助于癌症的发病机制，拟议的研究有明确的翻译 本案无关 上述工作将由内科/科的佩里博士执行。 耶鲁大学医学院内分泌学，在导师Gerald博士的指导下 舒尔曼，共同导师博士苏珊凯奇，和合作者博士道格拉斯罗斯曼和迈克尔波拉克。的 这里的研究是精心设计的，以扩大佩里博士的技术技能，以及磨练她的武器库。 科学推理，并提供职业发展培训，使她成为助理教授 在K99阶段结束时（K99/R 00奖励的第2年之后），并在 R 00阶段结束（K99/R 00奖项第5年）。这些目标将通过佩里博士的 计划，在本申请中描述，执行研究;经常与她的导师，合作者， 以及耶鲁大学其他具有研究兴趣或与这些研究相关的技术技能的教师; 完成课程;参加科学会议。