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

摘要 老龄化是许多常见疾病的最大风险因素，这些疾病给公共卫生造成了负担。这一行动的主要目标是 应用于了解由皮肤有害变化引起的年龄相关疾病的发病机制。 细胞外基质(ECM)微环境。这个应用程序采用了新的加速皮肤的鼠标模型 结缔组织衰老，因此满足了NIH确定的开发和表征结缔组织衰老的需求 衰老研究的动物模型(FOA PA-13-155)。 真皮构成皮肤的主体，赋予皮肤力量和弹性。真皮主要由以下成分组成 胶原性ECM。这种细胞外基质由成纤维细胞产生、组织和维持。我们最近的研究表明，真皮 在活体老化的人类皮肤中，成纤维细胞表达一种名为CCN1的蛋白质水平升高。我们发现升高的CCN1 导致成纤维细胞表达大量分泌蛋白的水平变化，对皮肤功能产生有害影响。 CCN1诱导的改变包括：1)胶原生成减少，导致真皮变薄；2)升高 胶原降解酶，导致细胞外基质碎裂；以及3)促炎症细胞因子水平增加， 促进衰老相关的炎症(发炎)。重要的是，这些由CCN1诱导的改变是主要的 人体老化皮肤的特征。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，我们建立了CCN1表达增加的转基因小鼠模型(CCN1ol-TG)。 成纤维细胞。这些小鼠表现出加速衰老和AADM。此外，这些小鼠表现出显著的增加 对皮肤肿瘤的易感性。根据我们的发现，我们假设与年龄相关的CCN1升高 真皮成纤维细胞引起AADM，AADM促进皮肤老化和与年龄相关的皮肤病。 特定目标1将检验健康的年轻皮肤微环境作为肿瘤抑制因子的假设，而 AADM具有肿瘤促进剂的作用。特异性靶点2将确定CCN1促进的分子机制 AADM。特定目标3将利用基于机制的干预来抑制CCN1诱导的AADM和皮肤癌 队形。 这一建议具有创新性和高度影响力，因为它：1)利用新的老鼠模型来研究新的概念 老龄化，即AADM及其在衰老和老年相关疾病中的作用，以及2)突出了相互作用的重要性 衰老过程中细胞外微环境与细胞功能衰退之间的关系。

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.