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.

项目摘要这项K99/R00建议中的研究和职业发展/培训活动旨在为PI装备雷切尔·佩里（Rachel Perry）博士，具有技术和科学专业知识以及成为独立的经验研究人员探索肿瘤代谢的话题。为此，佩里博士将在体内开发和优化，离体，体外磁共振和质谱法，以建模糖酵解和氧化结肠癌和肝癌的小鼠模型以及肿瘤浸润的T细胞中的代谢。这些研究旨在识别高胰岛素血症的机制被确定为结肠癌风险和进展的有力贡献 - 可能会促进肿瘤的生长。老鼠随后将结肠癌肿瘤用新型热剂进行治疗，一种受控释放线粒体质子团（CRMP），逆转高胰岛素血症及其对肿瘤进展的影响将确定代谢通量率，将改变的底物氧化速率和/或胰岛素信号传导相关联具有肿瘤生长的肿瘤的标记。然后，我们将用非酒精性脂肪性肝炎（NASH）治疗小鼠 - 与CRMP相关的肝细胞癌（HCC）。因为我们最近表明了这个代理逆转纳什纤维化，这些实验将测试逆转纳什的假设会减慢肿瘤生长，CRMP可能是减慢HCC进展的有吸引力的治疗选择。我们还将评估与正常生活相比使用体内和Ex Vivo NMR/质谱技术，以及CRMP对这些通量的影响。因为某些癌症与胰岛素抵抗/高胰岛素血症有关肝病和纳什（Nash 这些因素可能导致癌症发病机理，并且拟议的研究具有明确的翻译关联。上述工作将由佩里博士在内科/部门/部门进行耶鲁大学医学院的内分泌学，在她的心态的监督下，杰拉尔德博士 Shulman，Co-Mentor Susan Kaech博士和合作者Drs。道格拉斯·罗斯曼（Douglas Rothman）和迈克尔·波拉克（Michael Pollak）。这本文的研究经过精心设计，以扩大佩里博士的技术技能武器库以及亲爱的她科学推理并提供职业发展培训，使她成为一名助理教授在K99阶段结束时（K99/R00奖的第二年之后），并申请独立R01资金 R00阶段的结束（在K99/R00奖的第5年）。这些目标将通过佩里博士实现在本应用程序中描述的计划进行研究；经常与她的导师，合作者会面以及与这些研究相关的研究兴趣或技术技能的耶鲁教师的其他成员；完整的课程工作；并参加科学会议。