The Aging Cutaneous Microenvironment and Cancer Initiation
老化的皮肤微环境与癌症发生
基本信息
- 批准号:10659237
- 负责人:
- 金额:$ 42.86万
- 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:2021-09-30 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAccountingAddressAgeAgingAmericanCOL1A2 geneCarcinomaCell Culture TechniquesCutaneousDermalDermisDevelopmentDiagnosisDiseaseElderlyEpitheliumExhibitsExtracellular MatrixExtracellular Matrix ProteinsFibroblastsFunding OpportunitiesGene DeletionGenetically Engineered MouseGoalsGrowth FactorHGF geneHumanIncidenceIndividualInflammatoryInterventionLinkMalignant NeoplasmsModelingMolecularMusMutationNamesNational Cancer InstituteNational Institute on AgingPathway interactionsPeptide HydrolasesPersonsPhenotypePhysiologicalProductionProteinsPublishingRepressionSkinSkin AgingSkin CancerSkin CarcinogenesisSkin NeoplasmsSourceTP53 geneTestingTissuesage relatedagedautocrinecancer initiationcancer preventioncancer typecytokinedriver mutationkeratinocytemouse modelnotch proteinnovelnovel therapeutic interventionparacrinesecretory proteinsenescencetooltumor initiationtumorigenesis
项目摘要
ABSTRACT
Cancer is clearly a disease of aging. This connection between aging and cancer incidence is especially
true in the case of skin cancer, which is the most common form of human cancer, accounting for more
than all other cancers combined in USA. The major objective of this application is to gain understanding
of cellular and molecular mechanisms that link age-related skin changes to the initiation of skin cancer.
This application is based on our findings that fibroblasts in aged human skin express elevated levels of a
matricellular protein named CCN1, and that elevated CCN1 acts to deleteriously alter the dermal
compartment of skin to create a microenvironment that enhances cancer initiation. Based on these
observations, we have created genetically modified mice that express elevated levels of CCN1 selectively
in dermal fibroblasts (source of elevated CCN1 in aged human skin). These mice exhibit strikingly
accelerated dermal aging and display multiple hallmarks of aging that are seen in human skin. Importantly,
mice that express elevated levels of CCN1 in the dermis also have a high propensity for skin tumor
initiation. These results provide direct support for the overarching hypothesis of this application; that age-
related changes in the dermal microenvironment, driven by fibroblast expression of CCN1, create a dermal
microenvironment that enhances initiation of keratinocyte cancer. We propose to test this hypothesis with
the following specific aims. Aim 1: define the impact of CCN1-induced accelerated dermal aging on
keratinocyte cancer initiation. Aim 2: test the hypothesis that activation of the hepatocyte growth factor
pathway by the CCN1-induced dermal aging microenvironment drives keratinocyte cancer initiation. Aim
3: using targeted gene deletion, test the requirement for CCN1 expression in dermal fibroblasts for the
development of an aging-related dermal microenvironment and initiation of keratinocyte cancer. The aims
of this proposal directly address the objectives of the National Cancer Institute/National Aging Institute
Funding Opportunity Announcement to understand mechanisms by which age-related alterations in the
cellular niche/microenvironment contribute to cancer initiation.
摘要
癌症显然是一种衰老疾病。衰老和癌症发病率之间的这种联系尤其重要。
皮肤癌是人类癌症中最常见的一种,
比美国所有其他癌症加起来还要多本申请的主要目的是了解
细胞和分子机制,将年龄相关的皮肤变化与皮肤癌的发生联系起来。
该应用基于我们的发现,即老年人皮肤中的成纤维细胞表达升高水平的
一种名为CCN 1的基质细胞蛋白,CCN 1的升高会导致皮肤
皮肤的一个区室,以创造一个微环境,增强癌症的启动。基于这些
通过观察,我们创造了转基因小鼠,选择性地表达高水平的CCN 1
在真皮成纤维细胞中(老年人皮肤中CCN 1升高的来源)。这些老鼠表现出惊人的
加速皮肤老化,并显示出在人类皮肤中看到的多种老化标志。重要的是,
在真皮中表达升高水平的CCN 1的小鼠也具有皮肤肿瘤的高倾向性
初始化。这些结果为本申请的总体假设提供了直接支持;年龄-
由成纤维细胞表达CCN 1驱动的真皮微环境的相关变化,
微环境,增强角质形成细胞癌的启动。我们建议用以下方法来检验这一假设:
以下具体目标。目的1:确定CCN 1诱导的加速皮肤老化对
角质形成细胞癌发生。目的2:验证肝细胞生长因子的激活
通过CCN 1诱导的皮肤老化微环境的信号通路驱动角质形成细胞癌的发生。目的
3:使用靶向基因缺失,测试CCN 1在真皮成纤维细胞中表达的需要,
老化相关的皮肤微环境的发展和角质形成细胞癌的发生。目标
该提案的目的是直接解决国家癌症研究所/国家老龄化研究所的目标
资助机会公告,以了解与年龄相关的改变的机制,
细胞生态位/微环境有助于癌症的发生。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Human Skin Aging and the Anti-Aging Properties of Retinol.
- DOI:10.3390/biom13111614
- 发表时间:2023-11-04
- 期刊:
- 影响因子:5.5
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{{ truncateString('ANDRZEJ A. DLUGOSZ', 18)}}的其他基金
The Aging Cutaneous Microenvironment and Cancer Initiation
老化的皮肤微环境与癌症发生
- 批准号:
10490433 - 财政年份:2021
- 资助金额:
$ 42.86万 - 项目类别:
The Aging Cutaneous Microenvironment and Cancer Initiation
老化的皮肤微环境与癌症发生
- 批准号:
10292761 - 财政年份:2021
- 资助金额:
$ 42.86万 - 项目类别:
Cell fate decisions in Merkel cell carcinoma initiation and maintenance
默克尔细胞癌发生和维持的细胞命运决定
- 批准号:
9973721 - 财政年份:2020
- 资助金额:
$ 42.86万 - 项目类别:
Cell fate decisions in Merkel cell carcinoma initiation and maintenance
默克尔细胞癌发生和维持的细胞命运决定
- 批准号:
10330465 - 财政年份:2020
- 资助金额:
$ 42.86万 - 项目类别:
Cell fate decisions in Merkel cell carcinoma initiation and maintenance
默克尔细胞癌发生和维持的细胞命运决定
- 批准号:
10549793 - 财政年份:2020
- 资助金额:
$ 42.86万 - 项目类别:
Probing the role of aging in basal cell carcinoma development and treatment response
探讨衰老在基底细胞癌发展和治疗反应中的作用
- 批准号:
9203505 - 财政年份:2016
- 资助金额:
$ 42.86万 - 项目类别:
Merkel cell polyomavirus T antigens in tumorigenesis
默克尔细胞多瘤病毒 T 抗原在肿瘤发生中的作用
- 批准号:
8833939 - 财政年份:2015
- 资助金额:
$ 42.86万 - 项目类别:
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