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

描述（由申请人提供）：皮肤作为保护屏障的适当功能取决于终末分化计划的成功完成。在伤口愈合过程中，观察到一系列事件以重建皮肤的屏障功能。在伤口后，皮肤立即产生炎症反应，然后合成新的结缔组织，上皮细胞再生以闭合伤口和瘢痕重塑。这个复杂的过程需要不同细胞类型之间的相互作用，必须在时间和空间上协调。半胱天冬酶-8条件性敲除小鼠的表型与伤口愈合过程具有相似性，因为存在导致干细胞快速增殖以闭合伤口的增加的信号。在该培训研究金的赞助下，将实现以下具体目标：1.建立小鼠模型，以确定caspase-8是否调节表皮发育和修复2。测试caspase-8消融是否与表皮过度增殖和炎症有关3.从培养的半胱天冬酶-8 KO角质形成细胞中分离导致伤口愈合期间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对抗疾病的原因。在癌性生长中，也可以看到这种特性，但调节这一过程的信号已经出错。此外，创伤的许多特征，如炎症和组织微环境的改变是癌症进展的促成因素。因此，了解刺激干细胞增殖的因素对我们反击这些细胞的能力至关重要。来自表皮外层的分泌因子向皮肤更深处发出信号以激活干细胞分裂的潜力同样将提供对抗皮肤癌症的可及靶点。

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.