Mitochondrial ROS Regulate Skin and Hair Homeostasis

描述（由申请人提供）：表皮是抵御外部微生物、化学和热损伤的第一道防线。表皮还保护我们免受过多的液体流失，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）经历持续的稳态更新。除了它的屏障功能，表皮最近已被报道是有机体氧传感器的一个组成部分。线粒体功能障碍可以表现在毛发和皮肤疾病中。此外，衰老与线粒体DNA内突变的增加有关，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。先前的报道表明，线粒体功能障碍导致活性氧（ROS）的高产生，从而导致DNA和其他细胞组分的氧化损伤并导致细胞死亡。然而，我们已经发表了大量文章，证明线粒体ROS作为信号分子调节缺氧诱导的基因表达和癌基因诱导的肿瘤细胞增殖。因此，我们赞成这样的想法，即如果线粒体功能障碍导致线粒体ROS产生减少，则细胞维持稳态和适应压力所必需的ROS介导的信号传导被禁用。基于我们以前的数据，我们将测试的假设，即线粒体产生的活性氧是需要表皮的稳态和功能，允许适当的分化。我们已经开发了两种条件性基因敲除小鼠模型，这将使我们能够诱导表皮中的线粒体功能障碍，同时维持或消除线粒体的ROS产生。 公共卫生相关性：这项资助将测试线粒体ROS是否作为调节头发和皮肤稳态的正信号分子。

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. PUBLIC HEALTH RELEVANCE: This grant will test whether mitochondria ROS serve as positive signaling molecules regulating hair and skin homeostasis.