Impact of circadian disruption on pancreatic cancer development and progression

昼夜节律紊乱对胰腺癌发生和进展的影响

基本信息

  • 批准号:
    10531625
  • 负责人:
  • 金额:
    $ 25.13万
  • 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:
    2021-12-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

Abstract Shift work with resulting circadian disruption is increasingly recognized as a major environmental health hazard. In view of the prevalence of shift work in Western societies, investigation of the role played by circadian disruption should be assessed in many diseases. In addition to well-demonstrated effects on metabolism/ obesity and mental health, shift work has been classified as a Type 2A “probable carcinogen.” Recent work shows that environmental or genetic disruption of circadian rhythm can promote the development of lung cancer in mouse models of the disease. We seek to conduct similar studies, to assess whether circadian disruption impacts the development and/or progression of pancreatic cancer. It is estimated that pancreatic cancer will claim the lives of almost 48,000 people in 2021, making it the third-leading cause of cancer-related deaths in the United States. The disease carries a very dismal prognosis with median survival of approximately 8 months. This dire prognosis reflects the advanced stage of disease at diagnosis and the resistance of pancreatic cancer to currently employed treatment regimens, underscoring the need for a deeper understanding of the molecular underpinnings of the disease. Such understanding will increase the ability to develop novel effective therapeutic strategies. Given the number of individuals who perform shift work, understanding whether circadian disruption enhances pancreatic tumor initiation and/or progression, and characterizing the factors involved in this process is of great significance. This proposal will therefore directly test the hypothesis that circadian disruption enhances pancreatic cancer development and progression. In the first specific aim, we will test the hypothesis that circadian disruption induced by altered lighting protocols promotes the development of pancreatic cancer precursor lesions called pancreatic intraepithelial neoplasms (PanINs) in the validated FSF-KrasG12D;Pdx1-flp (KF) mouse model. We will further assess whether circadian disruption promotes progression to invasive carcinoma in this model, as well as in the FSF- KrasG12D;Trp53FRT/+;Pdx1-flp (KPF) model. To gain mechanistic insight into how circadian disruption promotes pancreatic tumorigenesis, we will additionally perform metabolic assessments of tumor-bearing mice. We will also subject a subset of tumors to single-cell RNA sequencing to identify gene expression changes that are specifically associated with tumors induced following circadian disruption. In the second aim, we will test the hypothesis that genetic disruption of normal circadian rhythms promotes the development and progression of pancreatic tumors. We will generate compound genetic mouse strains bearing the tumor-promoting Kras and Trp53 alleles in combination with neuron-specific deletion of Bmal1, previously shown to disrupt normal circadian rhythm. Parallel evaluation of metabolic and gene expression changes induced in these mice, when combined with the data from Aim 1, will allow the robust identification of genes and pathways to prioritize for future studies. Collectively, the proposed studies will elucidate the potential contributions of circadian disruption to pancreatic cancer development and progression. They will also lay the foundation for future studies that will interrogate the potential mechanisms in depth, thereby leading to novel prevention and therapeutic approaches.
摘要

项目成果

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BRIAN C LEWIS其他文献

BRIAN C LEWIS的其他文献

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{{ truncateString('BRIAN C LEWIS', 18)}}的其他基金

Targeting MTOR signaling in pancreatic cancer
靶向胰腺癌中的 MTOR 信号传导
  • 批准号:
    10367271
  • 财政年份:
    2022
  • 资助金额:
    $ 25.13万
  • 项目类别:
Targeting MTOR signaling in pancreatic cancer
靶向胰腺癌中的 MTOR 信号传导
  • 批准号:
    10617656
  • 财政年份:
    2022
  • 资助金额:
    $ 25.13万
  • 项目类别:
Impact of circadian disruption on pancreatic cancer development and progression
昼夜节律紊乱对胰腺癌发生和进展的影响
  • 批准号:
    10373645
  • 财政年份:
    2021
  • 资助金额:
    $ 25.13万
  • 项目类别:
IMSD at the University of Massachusetts Medical School
马萨诸塞大学医学院 IMSD
  • 批准号:
    10553216
  • 财政年份:
    2020
  • 资助金额:
    $ 25.13万
  • 项目类别:
IMSD at the University of Massachusetts Medical School
马萨诸塞大学医学院 IMSD
  • 批准号:
    10093106
  • 财政年份:
    2020
  • 资助金额:
    $ 25.13万
  • 项目类别:
Pathway to graduate study post-baccalaureate training program
研究生学习途径 学士学位后培训计划
  • 批准号:
    10080738
  • 财政年份:
    2018
  • 资助金额:
    $ 25.13万
  • 项目类别:
Pathway to graduate study post-baccalaureate training program
研究生学习途径 学士学位后培训计划
  • 批准号:
    10321902
  • 财政年份:
    2018
  • 资助金额:
    $ 25.13万
  • 项目类别:
Pathway to graduate study post-baccalaureate training program
研究生学习途径 学士学位后培训计划
  • 批准号:
    9416571
  • 财政年份:
    2018
  • 资助金额:
    $ 25.13万
  • 项目类别:
Pathway to graduate study post-baccalaureate training program
研究生学习途径 学士学位后培训计划
  • 批准号:
    10557496
  • 财政年份:
    2018
  • 资助金额:
    $ 25.13万
  • 项目类别:
Enhancing the success of underrepresented students in the biomedical sciences
提高生物医学领域代表性不足的学生的成功
  • 批准号:
    8844171
  • 财政年份:
    2015
  • 资助金额:
    $ 25.13万
  • 项目类别:

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