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: 10410587
• 负责人: GARY J FISHER
• 金额: $ 9.29万
• 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/10410587
• 关键词: Address; Age; Aging; Animal Model; Cell physiology; Collagen; Connective Tissue; Data; Dermal; Dermis; Development; Disease; Exhibits; Extracellular Matrix; Fibroblasts; Goals; Human; Inflammaging; Inflammation; Intervention; Molecular; Mus; Pathogenesis; Predisposition; Process; Production; Proteins; Public Health; Research; Risk Factors; Role; Skin; Skin Aging; Skin Cancer; Skin Neoplasms; Structure; Testing; Thinness; Transgenic Mice; Tumor Promoters; Tumor Suppressor Proteins; United States National Institutes of Health; age related; aged; base; burden of illness; collagenase; cytokine; extracellular; in vivo; innovation; mouse model; novel; resilience; skin disorder

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.

衰老是许多烧毁公共卫生的常见疾病的最大危险因素。这 该应用的主要目标是了解导致年龄相关疾病的发病机理 来自皮肤外基质（ECM）微环境的有害变化。这 应用员工的新型鼠标鼠标的加速皮肤连接的组织衰老和 因此，解决了NIH确定的对动物发展和表征的需求 老化研究模型（FOA PA-13-155）。 真皮包括大部分皮肤，并承认力量和弹性。真皮是主要的 由胶原性ECM组成。该ECM由成纤维细胞产生，组织和维护。 我们最近的研究表明，在体内老年人皮肤中，皮肤成纤维细胞表现出升高 称为CCN1的蛋白质水平。我们发现升高的CCN1导致成纤维细胞表达改变 众多分泌蛋白质的水平，这些蛋白质细致地影响皮肤功能。 CCN1引起的 改变包括：1）胶原蛋白产生减少，导致皮肤变薄； 2）高架 胶原蛋白的酶的水平，会导致ECM破碎； 3）水平增加 促炎细胞因子，促进相关感染（炎症）。 重要的是，这些CCN1引起的改变是老年人皮肤的主要特征。我们指的是 共同作为“与年龄相关的皮肤微环境（AADM）”进行这些改变。基于 在这些数据上，我们创建了一个转基因鼠标模型（CCN1COL -TG），并增加了 成纤维细胞表达CCN1。这些小鼠表现出加速的衰老和AADM。此外， 这些小鼠暴露于对皮肤肿瘤形成的敏感性显着提高。基于我们 调查结果，我们假设皮肤成纤维细胞与年龄相关的CCN1升高引起AADM， 可以促进皮肤老化和与年龄相关的皮肤疾病。具体目标1将检验假设 健康的年轻皮肤微环境可作为肿瘤抑制剂，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。具体目标3将利用基于机制的干预措施抑制CCN1诱导的AADM 和皮肤癌的形成。 该建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 研究衰老的新概念，即AADM及其在衰老和年龄相关疾病中的作用，以及 2）重点是细胞外微环境之间相互作用的重要性 在老化过程中细胞功能的下降。