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
• 负责人: MICHAEL R WILSON
• 金额: $ 11.87万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213512
• 关键词: Address; American Cancer Society; Aromatase; Automobile Driving; Award; Bioinformatics; Body Weight; Cancer Patient; Cell Death; Cell Survival; Cells; Cellular Stress Response; Cessation of life; DNA Sequence Alteration; Data; Development; Disease; Endometrial; Endometrial Carcinoma; Endometrium; Endoplasmic Reticulum; Environment; Epithelial; Estrogens; Faculty; Genetic; Genetically Engineered Mouse; Genomics; Goals; Growth; Gynecologic Oncology; Home; Homeostasis; Impairment; Incidence; Institution; Knowledge; Lead; Location; Malignant Neoplasms; Mentors; Metabolic; Metabolism; Michigan; Mutation; Myometrial; Normal Cell; Nucleotide Biosynthesis; Obesity; Pathogenesis; Pathway interactions; Phenotype; Phosphatidylinositols; Phosphotransferases; Play; Positioning Attribute; Postdoctoral Fellow; Pregnancy loss; Preventive measure; Preventive treatment; Proteins; Quality Control; Recurrence; Research; Research Institute; Research Personnel; Research Project Grants; Risk; Risk Factors; Role; Sampling; Schools; Secure; Signal Transduction; Somatic Mutation; Strategic Planning; Stress; Techniques; Testing; Therapeutic; Time; Training; Training and Education; United States; Universities; Uterus; Woman; XBP1 gene; anticancer research; base; biological adaptation to stress; cancer cell; cancer prevention; cancer risk; career; career development; driver mutation; endometrial cancer prevention; endoplasmic reticulum stress; expectation; experience; insight; mouse model; mutant; novel; novel strategies; nutrition; obese person; obesity genetics; pandemic disease; prevent; preventive intervention; programs; protein folding; proteostasis; response; tenure track; therapeutic target; transcription factor; tumor; tumor metabolism; tumorigenesis; uncontrolled cell growth

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.

项目摘要/摘要 研究项目：超重是导致高达20%的女性癌症死亡的一个因素。在……里面 特别是，子宫内膜癌(EC)的发病率在过去20年里稳步上升，同时伴随着 全球肥胖率的上升。EC是一种多因素疾病，肥胖和躯体驱动基因突变都起作用 因果角色。磷脂酰肌醇3-激酶(PI3K)途径的突变存在于超过80%的EC中。 然而，肥胖或PI3K通路突变单独对EC的发病是不够的。在以下方面存在重大差距 知识是基因突变如何改变肥胖女性的EC风险，证据表明是受损的 蛋白质质量控制作为一个重要的致病机制。肥胖导致系统内质网 应激(ERS)，由未折叠蛋白质的积累触发。如果不能实现蛋白质平衡， 未折叠的蛋白质反应会导致细胞死亡。由于芳香酶活性增加，肥胖会导致 “非对立雌激素”表型，它推动EC并导致子宫内的ERS。PI3K途径 拮抗ERS，并可能在这些条件下促进细胞存活。在这里，我建议研究一下休闲 肥胖与PI3K通路突变在EC发病机制中的关系我的中央 假设肥胖本身就会导致正常子宫的ERS，导致细胞死亡，但当PI3K 途径突变发生在肥胖女性的子宫内膜这种应激反应不会发生，结果 不受控制的细胞生长和癌症。在本申请中，我建议1)确定 子宫内膜中PI3K突变和ERS 2)雌激素诱导的ERS在EC中的作用 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·马瑟利博士的指导下。作为美国癌症学会博士后研究员罗纳德博士 Chandler的实验室，我揭示了子宫内膜上皮常见的体细胞突变的机制 导致EC发生肌层侵袭。我的目标是在一所领先的癌症学校获得终身教职。 研究机构，并制定一项研究计划，探索肥胖和 突变在EC发病机制中的作用，以确定积极预防干预的靶点。职业发展和 环境：K99/R00奖将确保我有必要的时间和培训来发展我的职业生涯 成功的独立调查员。我的导师将是罗纳德·钱德勒博士、何塞·特谢拉博士和维多利亚·贝博士- JUMP，妇科肿瘤学领域的专家。计划的活动将侧重于获得新的专业知识 肥胖研究。密歇根州立大学和范安德尔研究所是进行这项研究的理想地点 培训，是许多妇科肿瘤学、癌症新陈代谢、老鼠模型和 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 在新陈代谢和肥胖研究领域。