Does obesity influence protein quality control in endometrial cancer?

肥胖是否影响子宫内膜癌的蛋白质质量控​​制?

基本信息

  • 批准号:
    10376805
  • 负责人:
  • 金额:
    $ 11.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2022-11-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Research Project: Excess body weight is a contributing factor in up to 20% of all cancer deaths in women. In particular, endometrial cancer (EC) incidence has risen steadily over the past two decades concomitant with the rise in global obesity rates. EC is a multifactorial disease, as both obesity and somatic driver mutations play causal roles. Mutations in the phosphoinositide 3-kinase (PI3K) pathway are present in over 80% of all EC. However, obesity or PI3K pathway mutation alone are insufficient for EC pathogenesis. A major gap in knowledge is how genetic mutations alter EC risk in obese women, and evidence points towards impaired protein quality control as an important causal mechanism. Obesity causes systemic endoplasmic reticulum stress (ERS), which is triggered by the accumulation of unfolded proteins. If proteostasis cannot be achieved, the unfolded protein response induces cell death. Due to increased aromatase activity, obesity creates an “unopposed estrogen” phenotype, which drives EC and results in ERS in the uterus. The PI3K pathway antagonizes ERS and may promote cell survival under these conditions. Here, I propose to study the casual mechanistic relationship between obesity and PI3K pathway mutations in EC pathogenesis. My central hypothesis is that obesity alone causes ERS in the normal uterus, resulting in cell death, but when a PI3K pathway mutation occurs in the endometrium of obese women this stress response does not happen, resulting in uncontrolled cell growth and cancer. In this application, I propose to 1) Determine the relationship between PI3K mutation and ERS in the endometrium 2) Characterize the role of estrogen-induced ERS in EC 3) Determine the role for metabolism-induced ERS in EC prevention. Career Goals: My career will be focused on cancer research. In graduate school, I developed novel cancer therapeutics targeting nucleotide biosynthesis under the guidance of Dr. Larry Matherly. As an American Cancer Society Postdoctoral Fellow in Dr. Ronald Chandler’s lab, I uncovered the mechanism by which common somatic mutations in the endometrial epithelium result in myometrial invasion in EC. My goal is to secure a tenure-track faculty position at a leading cancer research institution, and to develop a research program exploring the relationship between obesity and mutation in EC pathogenesis to identify targets for active preventative intervention. Career Development and Environment: The K99/R00 award will secure the necessary time and training to develop my career as a successful independent investigator. My mentors will be Drs. Ronald Chandler, Jose Teixeira and Victoria Bae- Jump, experts in the field of gynecologic oncology. Activities planned will focus on gaining new expertise in obesity research. Michigan State University and the Van Andel Research Institute are the ideal location for this training, being home to many experts in gynecologic oncology, cancer metabolism, mouse modeling and bioinformatics. The Michigan Nutrition Obesity Research Center will provide additional education and training in the fields of metabolism and obesity research.
项目总结/摘要 研究项目:超重是导致女性所有癌症死亡人数中高达20%的一个因素。在 特别是,子宫内膜癌(EC)的发病率在过去二十年中稳步上升, 全球肥胖率的上升。EC是一种多因素疾病,因为肥胖和体细胞驱动突变都起作用。 因果作用超过80%的EC存在磷酸肌醇3-激酶(PI 3 K)途径的突变。 然而,单独的肥胖或PI 3 K通路突变不足以导致EC发病。一个主要的差距, 目前的知识是基因突变如何改变肥胖妇女的EC风险,证据表明, 蛋白质质量控制作为一个重要的因果机制。肥胖导致系统性内质网 应激(ERS),其由未折叠蛋白质的积累触发。如果不能实现蛋白质稳态, 未折叠的蛋白质反应诱导细胞死亡。由于芳香化酶活性增加,肥胖会产生 “非对抗性雌激素”表型,其驱动EC并导致子宫中的ERS。pi 3 k途径 拮抗ERS并可促进这些条件下的细胞存活。在这里,我建议研究休闲 肥胖与EC发病机制中PI 3 K通路突变之间的机制关系。我的中枢 一种假设是,肥胖单独导致正常子宫中的ERS,导致细胞死亡,但当PI 3 K 途径突变发生在肥胖妇女的子宫内膜中,这种应激反应不会发生, 不受控制的细胞生长和癌症。在本申请中,我建议1)确定以下关系: 子宫内膜中PI 3 K突变和ERS 2)表征雌激素诱导的ERS在EC中的作用3) 确定代谢诱导的ERS在EC预防中的作用。职业目标:我的职业生涯将专注于 癌症研究。在研究生院,我开发了针对核苷酸生物合成的新型癌症疗法, 在拉里·马瑟利医生的指导下作为美国癌症协会博士后研究员在罗纳德博士 在钱德勒的实验室里,我发现了子宫内膜上皮细胞中常见的体细胞突变 导致子宫内膜癌肌层浸润。我的目标是在一个领先的癌症研究所获得终身教职 研究机构,并制定一项研究计划,探索肥胖与 突变EC发病机制,以确定积极预防干预的目标。职业发展和 环境:K99/R 00奖将确保必要的时间和培训,以发展我的职业生涯, 成功的独立调查员我的导师将是罗纳德钱德勒、何塞特谢拉和维多利亚·裴博士- 跳,妇科肿瘤领域的专家。计划开展的活动将侧重于获得以下方面的新专门知识: 肥胖研究密歇根州立大学和货车安德尔研究所是这方面的理想地点 培训,拥有许多妇科肿瘤学、癌症代谢、小鼠建模和 生物信息学密歇根营养肥胖研究中心将提供额外的教育和培训 在新陈代谢和肥胖症研究领域。

项目成果

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MICHAEL R WILSON其他文献

MICHAEL R WILSON的其他文献

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{{ truncateString('MICHAEL R WILSON', 18)}}的其他基金

Does obesity influence protein quality control in endometrial cancer?
肥胖是否影响子宫内膜癌的蛋白质质量控​​制?
  • 批准号:
    10213512
  • 财政年份:
    2021
  • 资助金额:
    $ 11.82万
  • 项目类别:
Does obesity influence protein quality control in endometrial cancer?
肥胖是否影响子宫内膜癌的蛋白质质量控​​制?
  • 批准号:
    10732794
  • 财政年份:
    2021
  • 资助金额:
    $ 11.82万
  • 项目类别:

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