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下降中的作用，我们将分析早期生成的结缔组织特定的鼠模型，描述了增强的衰老并将其与本质上老化的对照小鼠进行比较。先前建立的鼠类衰老模型，具有结缔组织特异性的超氧化物歧化酶（SOD2）的特异性缺失，揭示了P16INK4A的上调，这是一种细胞周期抑制剂，可促进不可逆的成纤维细胞衰老，可促进胰岛素样生长因子1（IGF-1）的下降（IGF-1）（IGF-1），一种维持生长的生长和维持的生长。抑制IGF-1的释放构成了衰老成纤维细胞的衰老相关分泌表型（SASP）的关键标志。这样的老化计划的分期付款可以实施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，依赖氧化还原的转录因子同时诱导p16ink4a，同时抑制IGF-1。我们将遵循两个主要的相互联系的目标：1。确定氧化还原敏感转录因子Junb/ap1在皮肤衰老中的作用，并在组织下降中揭示其在组织下降中的作用方式，以及2。评估先天免疫系统的细胞，其衰老成纤维细胞的去除能力是否减少了衰老的纤维纤维纤维中的进一步积累。这两个研究重点是密切相关的，并且都有助于更好地理解富含结缔组织富有结缔器官中衰老细胞的积累。使用结缔组织特异性双SOD2/JUNB缺陷小鼠，我们将剖析依赖氧化还原的JUNB是否负责皮肤老化，这是否取决于选择性翻译并抑制IGF-1。通过缺乏天然杀伤细胞（NK细胞）或巨噬细胞的遗传操纵的鼠模型，我们将探索衰老细胞是否积聚在结缔组织中的富有器官中。此外，我们将采用策略，例如对年轻的NK细胞/巨噬细胞（骨髓）和天然IgM的产卵转移来更有效地去除衰老细胞，并研究SASP重新编程的可能性可能会减弱甚至还原延迟的衰老和延迟的衰老和皮肤同源性，包括干细胞恢复和增强恢复能力。该项目将有助于定义成纤维细胞衰老在皮肤老化以及其他富含结缔组织器官（例如骨骼和肌肉）上的核心作用。预期的结果将对有机体和有机体衰老/组织下降的适当干预措施发展前所未有的承诺。