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
- 来源:
- 关键词:ARNTL geneAccelerationAddressAffectAllelesCancer EtiologyCarcinogensCarcinomaCessation of lifeChronicCircadian DysregulationCircadian RhythmsClassificationCredentialingCuesDarknessDataDevelopmentDiagnosisDiseaseDisease ProgressionDisease modelEnvironmentEnvironmental HealthEvaluationFoundationsFutureGene ExpressionGene MutationGenesGeneticGenetically Engineered MouseHealthHealth HazardsHomeostasisHumanIncidenceIndividualIntraepithelial NeoplasiaInvestigationKRAS oncogenesisKRASG12DLesionLightLightingLinkMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasMental HealthMetabolicMetabolismModelingMolecularMouse StrainsMusMutationNeoplasm MetastasisNeuronsObesityOutcomePacemakersPancreasPancreatic Ductal AdenocarcinomaPathway interactionsPeripheralPersonsPhasePlayPrevalencePreventionPrevention strategyProbabilityProcessPrognosisProtocols documentationRegulationResearch PersonnelResistanceRoleSeriesSocietiesTestingTherapeuticTimeTissuesTreatment ProtocolsTumor PromotionUnited StatesWorkcancer preventioncarcinogenesiscircadiancircadian biologycircadian pacemakerepidemiology studygenome-wideimprovedin vivoinsightlung developmentmortalitymouse modelnovelpancreas developmentpancreatic ductal adenocarcinoma modelpancreatic neoplasmpancreatic tumorigenesisshift worksingle-cell RNA sequencingstatisticssuprachiasmatic nucleustherapeutically effectivetreatment strategytumortumor initiationtumor progression
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
期刊论文数量(0)
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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
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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
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- 批准号:
8844171 - 财政年份:2015
- 资助金额:
$ 25.13万 - 项目类别:
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