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

• 批准号: 9523384
• 负责人: GARY J FISHER
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/9523384
• 关键词: Address; Affect; Age; Age-Years; Aging; Aging-Related Process; 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; Institutes; Integrin alphaV; Intervention; Malignant Neoplasms; Mediating; MicroRNAs; Molecular; Mus; NIH Program Announcements; National Cancer Institute; Pathogenesis; Phenotype; Population; Predisposition; Prevention; 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

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 衰老是伯宁公共卫生许多常见疾病的最大危险因素。主要目标 应用是了解因皮肤的有害改变而引起的与年龄有关的疾病的发病机理 细胞外基质（ECM）微环境。该应用员工新颖的鼠标加速皮肤模型 结缔组织衰老，因此满足了NIH确定的需求，以发展和表征 衰老研究的动物模型（FOA PA-13-155）。 真皮包括大部分皮肤，并赋予力量和弹性。真皮主要由 胶原性ECM。该ECM由成纤维细胞产生，组织和维护。我们最近的研究表明真皮 在体内老年人皮肤中的成纤维细胞表达了一种称为CCN1的蛋白质的升高水平。我们发现CCN1升高 导致成纤维细胞表达众多分泌蛋白的水平改变，这些蛋白质会影响皮肤功能。 CCN1诱导的改变包括：1）胶原蛋白产生减少，导致皮肤变薄； 2）升高的水平 胶原蛋白降解酶，会导致ECM破碎； 3）促炎细胞因子的水平增加， 促进与衰老相关感染（炎症）。重要的是，这些CCN1引起的改变是主要的 老年人皮肤的特征。我们将这些改动集体称为“与年龄相关的皮肤微环境 （AADM）”。 基于这些数据，我们创建了一个转基因小鼠模型（CCN1COL-TG），并增加了CCN1的表达 成纤维细胞。这些小鼠表现出加速的衰老和AADM。另外，这些小鼠暴露了显着增加 对皮肤肿瘤形成的敏感性。根据我们的发现，我们假设通过 皮肤成纤维细胞会引起AADM，从而促进皮肤老化和与年龄有关的皮肤疾病。 特定的目标1将检验以下假设：健康的年轻皮肤微环境起抑制肿瘤的作用，而 AADM充当肿瘤启动子。特定的目标2将确定CCN1促进的分子机制 AADM。特定的目标3将利用基于机制的干预措施抑制CCN1诱导的AADM和皮肤癌 形成。 该提议具有创新性和高度影响力，因为它：1）利用新颖的鼠标模型来研究 衰老，即AADM及其在衰老和年龄相关疾病中的作用，以及2）将相互作用的重要性重点放在 在老化过程中细胞外微环境和细胞功能下降之间。