Mitochondrial ROS Regulate Skin and Hair Homeostasis

描述(申请人提供)：表皮是抵御外部微生物、化学物质和热损伤的第一道防护线。表皮还可以保护我们避免过度的水分流失，防止脱水。为了维持其保护功能，表皮及其附属物毛囊(HF)和皮脂腺(SG)经历了持续的动态平衡更新。除了它的屏障功能外，最近有报道称，表皮是生物体氧气感应机制的组成部分。线粒体功能障碍可表现在头发和皮肤疾病上。此外，衰老与线粒体DNA内突变的增加有关，这会导致线粒体功能障碍。线粒体DNA突变的基因工程小鼠表现出加速衰老的表型，包括脱发。以往的报道表明，线粒体功能障碍会导致大量产生活性氧物种(ROS)，导致DNA和其他细胞成分的氧化损伤，导致细胞死亡。然而，我们已经发表了大量关于线粒体ROS作为信号分子调控缺氧诱导的基因表达和癌基因诱导的肿瘤细胞增殖的文章。因此，我们倾向于这样的观点，即如果线粒体功能障碍导致线粒体ROS生成减少，那么ROS介导的细胞维持内稳态和适应应激所必需的信号就会被禁用。基于我们以前的数据，我们将通过允许适当的分化来检验线粒体产生的ROS是表皮动态平衡和功能所必需的假说。我们已经开发了两种条件性基因敲除小鼠模型，这两种模型将允许我们在维持或消除线粒体ROS产生的同时，诱导表皮线粒体功能障碍。

DESCRIPTION (provided by applicant): The epidermis is the first line of protection against external microbial, chemical, and thermal insults. The epidermis also protects us from excessive fluid loss, preventing dehydration. In order to maintain its protective function, epidermis and its appendages the hair follicles (HF) and sebaceous glands (SG) undergo continual homeostatic renewal. In addition to its barrier function, epidermis has been recently reported to be an integral part of the organismal oxygen sensing machinery. Mitochondrial dysfunction can manifest in hair and skin disorders. Moreover, aging is associated with an increase in mutations within mitochondrial DNA that leads to mitochondrial dysfunction. Genetically engineered mice with mutations in mitochondria DNA show an accelerated aging phenotype that includes hair loss. Previous reports suggest that mitochondrial dysfunction leads to high production of reactive oxygen species (ROS) leading to oxidative damage of DNA and other cellular components and resulting in cell death. However, we have published extensively on demonstrating that mitochondrial ROS serve as signaling molecules regulating hypoxia-induced gene expression and oncogene-induced tumor cell proliferation. Thus, we favor the idea that if mitochondrial dysfunction results in a decrease in mitochondrial ROS generation then ROS mediated signaling that is necessary for cells to maintain homeostasis and adapt to stress is disabled. Based on our previous data, we will test the hypothesis that mitochondrial generation of ROS is required for epidermal homeostasis and function by allowing for the proper differentiation. We have developed two conditional knockout mouse models which will allow us to induce mitochondrial dysfunction in the epidermis while either maintaining or eliminating ROS production from the mitochondria.