Aged tissue environments as drivers of oncogenic adaptation in hematopoiesis
Aged tissue environments as drivers of oncogenic adaptation in hematopoiesis
批准号:
10541835
负责人:
James V Degregori
金额:
$24.59万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-01-01 至 2024-11-30
关键词:
AgeAgingApicalAutomobile DrivingB-LymphocytesBloodBone MarrowCell CompartmentationCell Differentiation processCellsDevelopmentDirected Molecular EvolutionDiseaseElderlyEnvironmentEpigenetic ProcessEventEvolutionGene ExpressionGeneticGoalsHematopoiesisHematopoieticHematopoietic NeoplasmsHematopoietic stem cellsImpairmentIncidenceInflammationInflammatoryInterventionLifeLinkMalignant NeoplasmsModelingModificationMutateMutationNatural SelectionsOncogenicOrgan ModelPhenotypePopulationPreventionProcessRiskRisk ReductionRoleSignal TransductionSomatic CellTestingTimeTissuesage relatedagedaging populationbone agingcancer cellcancer riskcarcinogenicityenvironmental changefitnesshealthspanhematopoietic hierarchyhuman old age (65+)improvedleukemialeukemogenesismouse modelmutantpharmacologicpreventself-renewalstemstem cellssuccesstherapy developmenttumor microenvironmenttumorigenesis
中文摘要
随着年龄的增长,包括白血病在内的大多数癌症的风险呈指数级增加,
超过90%的癌症发生在50岁以后。这种联系主要归因于
致癌突变的逐渐积累。我们认为,
突变的贡献虽然是必要的,但不足以解释衰老在衰老中的作用。
白血病和其他癌症的发展。就像物种进化是由
环境的变化,选择适应性表型的人口,我们建议,
在老年时发生的组织变化是肿瘤发生的重要因素。在
特别是,老年人骨髓中的炎症增加,这有助于受损的
造血我们的中心假设是,炎症的年龄依赖性增加是
对于增强致癌突变的选择至关重要,抑制炎症可以
降低相关白血病的风险。我们以前用老鼠模型来展示
衰老和炎症的骨髓微环境降低了B细胞的适应性,
祖细胞,促进对特定适应性致癌事件的选择,导致增加
白血病发生在这里,我们将探讨老年微环境的改变如何促进
未成熟造血干细胞和早期祖细胞(HSPC)库中的肿瘤发生
造血系统的层次结构。我们认为C/EBPα和Myc活性是
老年骨髓微环境中的致癌选择,由于它们在
平衡HSPC分化和自我更新。因此,我们将制定干预措施,
微环境扰动使C/EBPα和Myc失调并导致肿瘤发生,
老年。为了验证我们的假设,我们将追求两个目标:1)确定是否老化和
炎症驱动HSPC隔室中的致癌适应,以及2)确定机制
HSPC池中肿瘤发生随年龄增长而增加的潜在原因。
通过确定微环境变化是否以及如何影响HSPC适应性,
因此,这些结果可以为老年人的致癌适应提供新的解释,
衰老和白血病风险之间的联系总之,我们提出的研究可以为以下问题提供答案:
基本问题:为什么随着年龄的增长,我们会患上更多的白血病?为什么特定的致癌性
在老年人的骨髓中选择的突变?我们能改变衰老相关的阳性
选择致癌事件,从而降低白血病风险?这些研究还可以确定
干预措施,降低老年造血系统恶性肿瘤的风险,
在骨髓微环境中促进肿瘤发生的炎症因子。
英文摘要
The risk of most cancers, including leukemias, increases exponentially as we age, with
over 90% of cancers occurring after the age of 50. This association has been primarily ascribed
to the gradual accumulation of oncogenic mutations throughout life. We contend that the
contribution of mutations, while necessary, is not sufficient to explain the role of aging in the
development of leukemias and other cancers. Just as species evolution has been driven by
environmental changes that select for adaptive phenotypes in populations, we propose that the
changes in our tissues occurring in old age are substantial contributors to oncogenesis. In
particular, inflammation increases in the bone marrow of the elderly, which contributes to impaired
hematopoiesis. Our central hypothesis is that aging-dependent increases in inflammation are
critical for enhancing selection for oncogenic mutations, and that dampening inflammation can
reduce the risk of the associated leukemias. We previously have used mouse models to show
that the aged and inflammatory bone marrow microenvironment reduces the fitness of B-cell
progenitors, promoting selection for particular adaptive oncogenic events, leading to increased
leukemogenesis. Here, we will explore how microenvironmental alterations in old age promote
oncogenesis in immature hematopoietic stem and early progenitor cell (HSPC) pools at the apex
of the hematopoietic hierarchy. We propose that C/EBPα and Myc activities are key hubs for
oncogenic selection in aged bone marrow microenvironments due to their critical roles in
balancing HSPC differentiation and self-renewal. Thus, we will develop interventions to reduce
microenvironmental perturbations that deregulate C/EBPα and Myc and lead to oncogenesis in
old age. To test our hypothesis, we will pursue two aims: 1) Determine whether aging and
inflammation drive oncogenic adaptation in the HSPC compartment and 2) Identify mechanisms
underlying increased oncogenesis with aging in HSPC pools.
By determining whether and how microenvironmental changes impact HSPC fitness and
thus oncogenic adaptation in old age, these results could provide a new explanation for links
between aging and leukemia risk. In all, our proposed studies could provide answers for
fundamental questions: Why do we get more leukemias as we age? Why are particular oncogenic
mutations selected for in the bone marrow of the elderly? Can we alter aging-associated positive
selection for oncogenic events and thus reduce leukemia risk? These studies could also identify
interventions that reduce the risk of hematopoietic malignancies of old age by manipulating
inflammatory factors that promote oncogenesis in the bone marrow microenvironment.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Impact of aging and clonal hematopoiesis on epigenetic heterogeneity, evolvability, and leukemogenesis
-
批准号:10700071
-
项目类别:
-
资助金额:$37.25万
-
财政年份:2021
-
负责人:James V Degregori
-
依托单位:
Impact of aging and clonal hematopoiesis on epigenetic heterogeneity, evolvability, and leukemogenesis
-
批准号:10353178
-
项目类别:
-
资助金额:$42.31万
-
财政年份:2021
-
负责人:James V Degregori
-
依托单位:
Impact of aging and clonal hematopoiesis on epigenetic heterogeneity, evolvability, and leukemogenesis
-
批准号:10493345
-
项目类别:
-
资助金额:$37.25万
-
财政年份:2021
-
负责人:James V Degregori
-
依托单位:
The impact of reduction of cellular senescence on age-related epigenetic heterogeneity
-
批准号:10830053
-
项目类别:
-
资助金额:$20.13万
-
财政年份:2021
-
负责人:James V Degregori
-
依托单位:
Aged tissue environments as drivers of oncogenic adaptation in hematopoiesis
-
批准号:10319990
-
项目类别:
-
资助金额:$25.02万
-
财政年份:2020
-
负责人:James V Degregori
-
依托单位:
Dissecting the Role of Inflammation in Smoking and Aging Associated Lung Cancers
-
批准号:10454873
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2019
-
负责人:James V Degregori
-
依托单位:
Dissecting the Role of Inflammation in Smoking and Aging Associated Lung Cancers
-
批准号:10683147
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2019
-
负责人:James V Degregori
-
依托单位:
Amy Briggs Diversity Supplement R01AG067584
-
批准号:10273522
-
项目类别:
-
资助金额:$3.06万
-
财政年份:2019
-
负责人:James V Degregori
-
依托单位:
Determining how aging-associated changes in the microenvironment contribute to leukemogenesis
-
批准号:10176352
-
项目类别:
-
资助金额:$43.92万
-
财政年份:2019
-
负责人:James V Degregori
-
依托单位:
Determining how aging-associated changes in the microenvironment contribute to leukemogenesis
-
批准号:10406996
-
项目类别:
-
资助金额:$37.72万
-
财政年份:2019
-
负责人:James V Degregori
-
依托单位:
Determining how aging-associated changes in the microenvironment contribute to leukemogenesis
-
批准号:10020895
-
项目类别:
-
资助金额:$37.83万
-
财政年份:2019
-
负责人:James V Degregori
-
依托单位:
Determining how aging-associated changes in the microenvironment contribute to leukemogenesis
-
批准号:10668637
-
项目类别:
-
资助金额:$6.19万
-
财政年份:2019
-
负责人:James V Degregori
-
依托单位:
Dissecting the Role of Inflammation in Smoking and Aging Associated Lung Cancers
-
批准号:9894635
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2019
-
负责人:James V Degregori
-
依托单位:
Dissecting the Role of Inflammation in Smoking and Aging Associated Lung Cancers
-
批准号:10265400
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2019
-
负责人:James V Degregori
-
依托单位:
Nrf2-mediated impaired hematopoietic stem cell fitness following irradiation
-
批准号:8813763
-
项目类别:
-
资助金额:$16.88万
-
财政年份:2014
-
负责人:James V Degregori
-
依托单位:
Aging-associated alterations in adaptive landscapes and the evolution of leukemia
-
批准号:8725101
-
项目类别:
-
资助金额:$30.95万
-
财政年份:2013
-
负责人:James V Degregori
-
依托单位:
Aging-associated alterations in adaptive landscapes and the evolution of leukemia
-
批准号:9086311
-
项目类别:
-
资助金额:$34.5万
-
财政年份:2013
-
负责人:James V Degregori
-
依托单位:
Aging-associated alterations in adaptive landscapes and the evolution of leukemia
-
批准号:8588008
-
项目类别:
-
资助金额:$31.4万
-
财政年份:2013
-
负责人:James V Degregori
-
依托单位:
Aging-associated alterations in adaptive landscapes and the evolution of leukemia
-
批准号:9278007
-
项目类别:
-
资助金额:$34.49万
-
财政年份:2013
-
负责人:James V Degregori
-
依托单位:
Aging-associated alterations in adaptive landscapes and the evolution of leukemia
-
批准号:8862436
-
项目类别:
-
资助金额:$34.5万
-
财政年份:2013
-
负责人:James V Degregori
-
依托单位:
海外基金