Control of aging and age-related diseases by extracellular matrix microenvironment

细胞外基质微环境控制衰老和年龄相关疾病

基本信息

批准号：
10163759
负责人：
GARY J FISHER
金额：
$ 31.98万
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：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163759
关键词：
Address Affect Age Age-Years Aging American Animal Model Applications Grants Biochemical Cancer Etiology Cell physiology Chronic Disease Collagen Collagen Fibril Connective Tissue Data Dermal Dermis Development Diagnosis Disease Elderly Epigenetic Process Exhibits Extracellular Matrix Fibroblasts Funding Opportunities Genetic Goals Homeostasis Human Impairment Individual Inflammaging Inflammation Integrin alphaV Intervention Malignant Neoplasms Mediating MicroRNAs Molecular Mus NIH Program Announcements National Cancer Institute National Institute on Aging Pathogenesis Phenotype Population Predisposition Prevention Process Production Proteins Public Health Quality of life Research Risk Factors Role Signal Transduction Skin Skin Aging Skin Cancer Skin Neoplasms Structure Testing Thinness Transgenic Mice Tumor Promoters Tumor Suppressor Proteins United States United States National Institutes of Health Xenograft procedure age related aged base burden of illness chemical carcinogen collagenase cytokine extracellular high risk in vivo innovation keratinocyte mouse model novel resilience skin disorder tumor ultraviolet irradiation

项目摘要

ABSTRACT Aging is the single largest risk factor for many common diseases that burden public health. The major goal of this application is to understand the pathogenesis of age-related diseases resulting from deleterious alterations of the dermal extracellular matrix (ECM) microenvironment. This application employs novel mouse models of accelerated skin connective tissue aging and therefore addresses a need identified by the NIH for development and characterization of animal models for aging research (FOA PA-13-155). The dermis comprises the bulk of skin and confers strength and resiliency. The dermis is primarily composed of collagenous ECM. This ECM is produced, organized and maintained by fibroblasts. Our recent studies reveal that dermal fibroblasts, in aged human skin in vivo, express elevated levels of a protein called CCN1. We find that elevated CCN1 causes fibroblasts to express altered levels of numerous secreted proteins that deleteriously impact skin function. CCN1-induced alterations include: 1) reduced collagen production, which causes dermal thinning; 2) elevated levels of collagen-degrading enzymes, which cause ECM fragmentation; and 3) increased levels of proinflammatory cytokines, which promote aging associated inflammation (inflammaging). Importantly, these CCN1-induced alterations are major features of aged human skin. We refer collectively to these alterations as “Age-Associated Dermal Microenvironment (AADM)”. Based on these data, we have created a transgenic mouse model (CCN1col-tg) with increased expression of CCN1 by fibroblasts. These mice display accelerated aging and AADM. In addition, these mice exhibit significantly increased susceptibility to formation of skin tumors. Based on our findings, we hypothesize that age-related elevation of CCN1 by dermal fibroblasts causes AADM, which promotes skin aging and age-related skin diseases. Specific Aim 1 will test the hypothesis that healthy young dermal microenvironment functions as tumor suppressor, while AADM act as a tumor promoter. Specific Aim 2 will determine molecular mechanisms by which CCN1 promotes AADM. Specific Aim 3 will utilize mechanism-based intervention to inhibit CCN1-induced AADM and skin cancer formation. This proposal is innovative and highly impactful because it: 1) utilizes novel mouse models to investigate new concepts of aging, i.e. AADM and its role in aging and age-related diseases, and 2) brings into focus the importance of the interplay between the extracellular microenvironment and decline of cell function during the aging process.

抽象的衰老是许多给公众健康带来负担的常见疾病的最大单一危险因素。应用是为了了解由真皮有害改变引起的与年龄相关的疾病的发病机制该应用采用新型小鼠皮肤加速模型。结缔组织老化，因此解决了 NIH 确定的开发和表征的需求用于衰老研究的动物模型（FOA PA-13-155）。真皮构成皮肤的大部分，赋予皮肤强度和弹性。真皮主要由以下物质组成。我们最近的研究表明，胶原 ECM 是由成纤维细胞产生、组织和维持的。在体内老化的人类皮肤中，成纤维细胞表达了一种称为 CCN1 的蛋白质，其水平升高。导致成纤维细胞表达大量分泌蛋白的水平发生改变，从而对皮肤功能产生有害影响。 CCN1 引起的改变包括：1) 胶原蛋白生成减少，导致真皮变薄；2) 胶原蛋白水平升高；胶原蛋白降解酶，导致 ECM 碎片；3) 促炎细胞因子水平增加，重要的是，这些 CCN1 诱导的改变是主要的。我们将这些变化统称为“与年龄相关的皮肤微环境”。（AADM）”。基于这些数据，我们通过以下方法创建了 CCN1 表达增加的转基因小鼠模型 (CCN1col-tg) 这些小鼠的成纤维细胞表现出加速衰老和 AADM。根据我们的研究结果，我们通过以下方法追踪了 CCN1 与年龄相关的升高。真皮成纤维细胞会引起AADM，从而促进皮肤老化和与年龄相关的皮肤病。具体目标 1 将检验健康的年轻真皮微环境具有肿瘤抑制作用的假设，而 AADM 作为肿瘤促进剂，具体目标 2 将确定 CCN1 促进的分子机制。 AADM。具体目标 3 将利用基于机制的干预来抑制 CCN1 诱导的 AADM 和皮肤癌形成。该提案具有创新性且极具影响力，因为它：1）利用新颖的小鼠模型来研究新概念衰老，即 AADM 及其在衰老和年龄相关疾病中的作用，2) 使人们关注相互作用的重要性衰老过程中细胞外微环境与细胞功能衰退之间的关系。