Role of pro-oxidative connective tissue in skin aging – Molecular mechanisms and therapeutic strategies

促氧化结缔组织在皮肤衰老中的作用 â 分子机制和治疗策略

• 批准号: 432048315
• 负责人: Professorin Dr. Karin Scharffetter-Kochanek
• 金额: --
• 依托单位: Universitätsklinik für Dermatologie und Allergologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432048315?language=en
• 关键词: Role; pro; oxidative; connective; tissue

To understand the role of fibroblasts in organ aging and tissue decline, we will analyze our earlier generated connective tissue specific murine model depicting enhanced aging and compare it to intrinsically aged control mice. The previously established murine aging model with a connective tissue specific deletion of the manganese superoxide dismutase (SOD2) revealed concomitant up-regulation of p16INK4A, a cell cycle inhibitor promoting irreversible fibroblasts senescence, and a profound decline of Insulin-like Growth Factor 1 (IGF-1), an important growth and tissue maintenance factor. Suppressed release of IGF-1 constitutes a key hallmark of the senescence-associated secretory phenotype (SASP) of senescent fibroblasts. The installment of such an aging program enforces severe connective tissue aging and overall skin aging. Indirect evidence of our laboratory suggests that a redox-dependent transcription factor concomitantly induces p16INK4A, while suppressing IGF-1. We here will follow two main interconnected objectives: 1. to establish the role of the redox sensitive transcription factor JunB/AP1 in skin aging and to unravel its mode of action in tissue decline, and 2. to assess whether cells of the innate immune system with reduced removal capacity of senescent fibroblasts are responsible for further accumulation of senescent fibroblasts in the skin of aged mice. These two research foci are intimately interrelated, and both contribute to a better understanding of enhanced accumulation of senescent cells in connective tissue rich organs. Using connective tissue specific double Sod2/JunB deficient mice, we will dissect whether redox-dependent JunB is responsible for skin aging and whether this depends on selective translation with suppression of IGF-1. By means of genetically manipulated murine models which lack natural killer cells (NK cells) or macrophages, we will explore whether senescent cells accumulate in connective tissue rich organ like skin. In addition, we will employ strategies, like adoptive transfer of young NK cells/macrophages (bone marrow) and natural IgM to more efficiently remove senescent cells and will study the likely possibility that reprogramming of the SASP will attenuate or even restore delayed aging and skin homoeostasis including stem cell renewal and enhanced regenerative capacity. This project will help to define the central role of fibroblast senescence on skin aging, and on other connective tissue rich organs, such as bone and muscle. The expected results will hold unprecedented promise for the development of appropriate interventions for organ and organismal aging/tissue decline.

为了了解成纤维细胞在器官衰老和组织衰退中的作用，我们将分析我们早期生成的描述衰老加速的结缔组织特异性小鼠模型，并将其与本质衰老的对照小鼠进行比较。先前建立的结缔组织特异性删除锰超氧化物歧化酶 (SOD2) 的小鼠衰老模型显示，p16INK4A（一种促进不可逆成纤维细胞衰老的细胞周期抑制剂）伴随上调，以及胰岛素样生长因子 1 (IGF) 的严重下降。 -1)，重要的生长和组织维持因子。 IGF-1 释放抑制是衰老成纤维细胞衰老相关分泌表型 (SASP) 的一个关键标志。这种老化程序的安装会导致严重的结缔组织老化和整体皮肤老化。我们实验室的间接证据表明氧化还原依赖性转录因子同时诱导 p16INK4A，同时抑制 IGF-1。我们将遵循两个相互关联的主要目标：1. 确定氧化还原敏感转录因子 JunB/AP1 在皮肤衰老中的作用，并揭示其在组织衰退中的作用模式，2. 评估先天免疫系统的细胞是否衰老成纤维细胞清除能力降低是导致衰老小鼠皮肤中衰老成纤维细胞进一步积累的原因。这两个研究焦点密切相关，都有助于更好地理解富含结缔组织的器官中衰老细胞积累的增强。使用结缔组织特异性双 Sod2/JunB 缺陷小鼠，我们将剖析氧化还原依赖性 JunB 是否导致皮肤衰老，以及这是否取决于选择性翻译和抑制 IGF-1。通过缺乏自然杀伤细胞（NK细胞）或巨噬细胞的基因操纵小鼠模型，我们将探讨衰老细胞是否在富含结缔组织的器官（如皮肤）中积累。此外，我们将采用年轻 NK 细胞/巨噬细胞（骨髓）和天然 IgM 的过继转移等策略来更有效地去除衰老细胞，并将研究 SASP 重新编程将减轻甚至恢复延迟衰老和皮肤的可能性。体内平衡包括干细胞更新和增强的再生能力。该项目将有助于确定成纤维细胞衰老对皮肤衰老以及其他富含结缔组织的器官（例如骨骼和肌肉）的核心作用。预期结果将为开发针对器官和组织衰老/组织衰退的适当干预措施带来前所未有的希望。