Regulation of tumor growth and metabolism by hyperinsulinemia

高胰岛素血症调节肿瘤生长和代谢

基本信息

批准号：
9981679
负责人：
Rachel Jamison Perry
金额：
$ 24.9万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981679
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 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 Obesity Epidemic 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 colon cancer risk 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 disease nonalcoholic steatohepatitis novel therapeutics outcome forecast oxidation professor stable isotope tumor tumor growth tumor metabolism tumor progression

项目摘要

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.

项目概要本 K99/R00 提案中的研究和职业发展/培训活动旨在装备 PI、 Rachel Perry 博士拥有技术和科学专业知识以及成为独立专家的经验为此，佩里博士将研究肿瘤代谢这一主题，并在体内进行开发和优化。体外和体外磁共振和质谱方法来模拟糖酵解和氧化结肠癌和肝细胞癌小鼠模型以及肿瘤浸润 T 细胞中的代谢。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——可能会促进小鼠肿瘤的生长。患有结肠癌的肿瘤将用一种新型治疗剂进行治疗，一种控释药物线粒体质子载体（CRMP），逆转高胰岛素血症，及其对肿瘤进展和的影响将确定代谢通量率，将改变的底物氧化率和/或胰岛素信号传导关联起来然后，我们将治疗患有非酒精性脂肪性肝炎（NASH）的小鼠。因为我们最近证明了这种药物与肝细胞癌 (HCC) 相关。逆转 NASH 纤维化，这些实验将检验逆转 NASH 会减缓肿瘤生长的假设增长，并且 CRMP 可能是减缓 HCC 进展的一种有吸引力的治疗选择。与正常肝脏相比，患有 HCC 的小鼠肝脏中可能发生的代谢通量率的变化使用体内和离体 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，非酒精性脂肪肝病和 NASH，当前的肥胖流行需要努力了解其机制这些因素可能有助于癌症发病机制，并且拟议的研究具有明确的转化作用关联。上述工作将由内科/科的 Perry 博士进行在耶鲁大学医学院内分泌科，在导师 Gerald 博士的指导下 Shulman、联合导师 Susan Kaech 博士以及合作者 Douglas Rothman 和 Michael Pollak 博士。研究经过精心设计，旨在扩大佩里博士的技术技能库并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（K99/R00 奖励的第 2 年之后），并在 R00 阶段结束（K99/R00 奖的第 5 年）这些目标将通过 Perry 博士的实现来实现。本申请中描述的计划进行研究；经常与她的导师、合作者会面，以及具有与这些研究相关的研究兴趣或技术技能的耶鲁大学教师的其他成员；完成课程作业；并参加科学会议。