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

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。这个 此应用程序的主要目标是了解与年龄相关的疾病的发病机制 由于真皮细胞外基质(ECM)微环境的有害变化。这 应用新的小鼠皮肤结缔组织加速老化模型和 因此解决了美国国立卫生研究院确定的对动物发育和特征的需求 老龄化研究模型(FOA PA-13-155)。 真皮构成皮肤的主体，赋予皮肤力量和弹性。真皮主要是 由胶原性ECM组成。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，在活体老年人皮肤中，真皮成纤维细胞表达上调 一种名为CCN1的蛋白质水平。我们发现CCN1升高导致成纤维细胞表达改变 大量分泌的蛋白质水平有害地影响皮肤功能。CCN1诱导 改变包括：1)胶原生成减少，导致真皮变薄；2)升高 导致细胞外基质碎裂的胶原降解酶水平；以及3)水平升高 促炎症细胞因子，促进衰老相关炎症(炎症)。 重要的是，这些由CCN1诱导的变化是人类衰老皮肤的主要特征。我们是指 将这些变化统称为“年龄相关真皮微环境(AADM)”。基座 在这些数据的基础上，我们建立了一个转基因小鼠模型(CCN1ol-TG)，并增加了 成纤维细胞表达CCN1的实验研究这些小鼠表现出加速衰老和AADM。此外, 这些小鼠表现出对皮肤肿瘤形成的显著增加的敏感性。基于我们的 结果，我们假设真皮成纤维细胞与年龄相关的CCN1的升高导致了AADM， 促进皮肤老化和与年龄相关的皮肤病。具体目标1将检验这一假设 健康的年轻真皮微环境起肿瘤抑制作用，而AADM起作用 肿瘤促进剂。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 以及皮肤癌的形成。 这一建议具有创新性和高度的影响力，因为它：1)利用新的鼠标模型来 研究老龄化的新概念，即AADM及其在老龄化和与年龄相关的疾病中的作用，以及 2)突出了细胞外微环境之间相互作用的重要性 衰老过程中细胞功能下降。

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.