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

老龄化是造成公共卫生负担的许多常见疾病的最大风险因素。的 本申请的主要目标是了解年龄相关疾病的发病机制， 皮肤细胞外基质（ECM）微环境的有害改变。这 本申请采用了加速皮肤结缔组织老化的新小鼠模型， 因此，解决了NIH确定的开发和表征动物 老化研究模型（FOA PA-13 - 155）。 真皮构成皮肤的主体并赋予强度和弹性。真皮主要是 由胶原ECM组成。这种ECM由成纤维细胞产生、组织和维持。 我们最近的研究表明，在体内老年人皮肤中，真皮成纤维细胞表达升高， 一种叫做CCN 1的蛋白质。我们发现CCN 1的升高会导致成纤维细胞表达改变的 许多分泌蛋白质的水平，有害地影响皮肤功能。CCN 1诱导 改变包括：1）减少胶原蛋白的产生，这导致皮肤变薄; 2）增加胶原蛋白的产生，这导致皮肤变薄。 胶原降解酶的水平，其导致ECM片段化;和3）增加的水平 促炎细胞因子，促进衰老相关的炎症（炎症）。 重要的是，这些CCN 1诱导的改变是老年人皮肤的主要特征。我们指 这些变化统称为“年龄相关的皮肤微环境（AADM）”。基于 根据这些数据，我们建立了一个转基因小鼠模型（CCN 1col ‐tg）， 成纤维细胞CCN 1的表达。这些小鼠显示加速老化和AADM。此外，本发明还提供了一种方法， 这些小鼠表现出对皮肤肿瘤形成的显著增加的易感性。基于我们 研究结果，我们假设皮肤成纤维细胞引起的年龄相关的CCN 1升高导致AADM， 会促进皮肤老化和与年龄相关的皮肤病具体目标1将检验假设 健康年轻的皮肤微环境作为肿瘤抑制因子，而AADM作为肿瘤抑制因子， 肿瘤促进剂。具体目标2将确定CCN 1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CCN 1诱导的AADM 和皮肤癌的形成。 该提案具有创新性和高度影响力，因为它：1）利用新型小鼠模型， 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)使人们关注细胞外微环境之间相互作用的重要性， 以及衰老过程中细胞功能的衰退。

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.