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：
ANDRZEJ A. DLUGOSZ
金额：
$ 42.86万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
https://reporter.nih.gov/project-details/10659237
关键词：
Acceleration Accounting Address Age Aging American COL1A2 gene Carcinoma Cell Culture Techniques Cutaneous Dermal Dermis Development Diagnosis Disease Elderly Epithelium Exhibits Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Funding Opportunities Gene Deletion Genetically Engineered Mouse Goals Growth Factor HGF gene Human Incidence Individual Inflammatory Intervention Link Malignant Neoplasms Modeling Molecular Mus Mutation Names National Cancer Institute National Institute on Aging Pathway interactions Peptide Hydrolases Persons Phenotype Physiological Production Proteins Publishing Repression Skin Skin Aging Skin Cancer Skin Carcinogenesis Skin Neoplasms Source TP53 gene Testing Tissues age related aged autocrine cancer initiation cancer prevention cancer type cytokine driver mutation keratinocyte mouse model notch protein novel novel therapeutic intervention paracrine secretory protein senescence tool tumor initiation tumorigenesis

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.

抽象的癌症显然是衰老的疾病。尤其是衰老与癌症发病率之间的这种联系在皮肤癌的情况下，这是最常见的人类癌症形式比在美国合并的所有其他癌症。该应用的主要目的是获得理解将与年龄相关的皮肤联系起来的细胞和分子机制与皮肤癌的启动。该应用是基于我们的发现，即老年人皮肤的成纤维细胞表达升高的水平名为CCN1的母细胞蛋白，该升高的CCN1作用于有害的皮肤皮肤的隔室创造了一种微环境，可增强癌症的起步。基于这些观察结果，我们创建了转基因的小鼠，以选择性地表达CCN1的升高水平在皮肤成纤维细胞中（陈年人皮肤中CCN1升高的来源）。这些小鼠表现出惊人的表现加速皮肤衰老并显示出在人皮肤中看到的多种衰老标志。重要的是，表达真皮中CCN1水平升高的小鼠对皮肤肿瘤的倾向也很高引发。这些结果为该应用程序的总体假设提供了直接支持。那个年龄 - 由CCN1的成纤维细胞表达驱动的真皮微环境的相关变化，形成真皮增强角质形成癌开始的微环境。我们建议用以下特定目标。目标1：定义CCN1诱导的加速皮肤衰老对角质形成细胞癌的启动。目标2：检验肝细胞生长因子激活的假设 CCN1诱导的皮肤衰老微环境的途径驱动角质细胞癌的启动。目的 3：使用靶向基因缺失，测试皮肤成纤维细胞中CCN1表达的需求与衰老相关的皮肤微环境的发展和角质形成癌的启动。目的该提案直接解决国家癌症研究所/国家老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利基/微环境有助于癌症的启动。