Novel Role for Caspase-8 in Epidermal Homeostasis and Wound Healing

描述(申请人提供)：皮肤作为保护性屏障的正确功能取决于终端分化程序的成功完成。在伤口愈合过程中，观察了一系列事件，以重建皮肤的屏障功能。伤口后，皮肤立即产生炎症反应，然后合成新的结缔组织，上皮细胞重新生长以闭合伤口，并重塑疤痕。这一复杂的过程需要不同细胞类型之间的相互作用，这些相互作用必须在时间和空间上协调。Caspase-8条件性基因敲除小鼠的表型与伤口愈合过程有相似之处，因为有一个增加的信号导致干细胞快速增殖以关闭伤口。在该培训基金的主持下，将追求以下具体目标：1.建立小鼠模型，以确定caspase-8是否调节表皮的发育和修复2.测试caspase-8消融是否与表皮过度增殖和炎症有关3.从培养的caspase-8 KO角质形成细胞中分离出在伤口愈合过程中导致角质形成细胞增殖增加的因子。干细胞最显著的特征之一是它们的增殖能力，这也是这些细胞很有希望用于抗击疾病的原因之一。在癌变的生长过程中，也可以看到这种特性，但调节这一过程的信号出现了错误。此外，创伤的许多特征，如炎症和组织微环境的改变，都是导致癌症进展的因素。因此，对刺激干细胞增殖的因素的了解对我们反击这些细胞的能力至关重要。表皮外层的一种分泌因子向更深的皮肤发出信号以激活干细胞分裂的潜力，也同样为对抗皮肤癌提供了一个可获得的靶点。

DESCRIPTION (provided by applicant): Proper function of skin as a protective barrier depends on the successful completion of the terminal differentiation program. During the wound healing process, a series of events are observed in order to re- establish the barrier function of the skin. Immediately after a wound, the skin responds by producing an inflammatory response, followed by synthesis of new connective tissue, epithelial repopulation to close the wound and scar-remodeling. This complex process requires interactions between different cell types that must be temporally and spatially coordinated. The phenotype of caspase-8 conditional knockout mice share a similarity with the wound healing process in that there is an increased signal leading to the rapid proliferation of stem cells to close the wound. Under the auspices of this training fellowship, the following specific aims will be pursued: 1. Develop mouse models to determine whether caspase-8 regulates epidermal development and repair 2. Test whether caspase-8 ablation links epidermal hyperproliferation and inflammation 3. Isolate factors from cultured caspase-8 KO keratinocytes that lead to increased proliferation of keratinocytes during wound healing. One the most notable characteristic of stem cells and the reason there is much hope for these cells to be used to combat disease is their capacity to proliferate. In a cancerous growth, this property is also seen but the signals that regulate this process have gone awry. Moreover, many characteristics of wounding such as inflammation and alterations in tissue microenvironment are contributing factors of cancer progression. Therefore, knowledge of factors that stimulate stem cells to proliferate is vital to our ability to counterattack these cells. The potential of a secreted factor from the outer layer of the epidermis signaling deeper into the skin to activate stem cell division would likewise provide an accessible target to combat cancers of the skin.