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

Caspase-8 在表皮稳态和伤口愈合中的新作用

• 批准号: 8032440
• 负责人: Pedro Lee
• 金额: $ 0.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032440
• 关键词: Ablation; Affect; Cancerous; Cells; Characteristics; Cicatrix; Complex; Connective Tissue; Cutaneous; Development; Disease; Epidermis; Epithelial; Event; Fellowship; Goals; Growth; Growth Factor; Homeostasis; Immune; Inflammation; Inflammatory Response; Knockout Mice; Knowledge; Lead; Link; Maintenance; Mesenchymal; Modeling; Molecular; Mus; Natural regeneration; Paracrine Communication; Phenotype; Process; Proliferating; Property; Role; Series; Signal Transduction; Skin; Skin Cancer; Stem cells; Testing; Tissues; Training; Wound Healing; caspase-8; cell type; combat; keratinocyte; mouse model; novel; programs; repaired; stem cell division; tumor progression; wound

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.

描述（由申请人提供）：皮肤作为保护屏障的正常功能取决于终端分化计划的成功完成。在伤口愈合过程中，为了重建皮肤的屏障功能，观察了一系列的事件。受伤后，皮肤立即产生炎症反应，随后合成新的结缔组织，上皮细胞再生以关闭伤口和疤痕重塑。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。caspase-8条件敲除小鼠的表型与伤口愈合过程有相似之处，即有增加的信号导致干细胞快速增殖以关闭伤口。在这项培训研究金的主持下，将实现下列具体目标：建立小鼠模型以确定caspase-8是否调节表皮发育和修复2。检测caspase-8消融是否与表皮增生和炎症相关从培养的caspase-8 KO角质形成细胞中分离出导致伤口愈合过程中角质形成细胞增殖增加的因子。干细胞最显著的特征之一，也是这些细胞被用来对抗疾病的希望很大的原因，是它们的增殖能力。在癌症生长中，这种特性也可以看到，但调节这一过程的信号已经出错了。此外，损伤的许多特征，如炎症和组织微环境的改变，都是促进癌症进展的因素。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。来自表皮外层的一种分泌因子可能会向皮肤深处发出信号，从而激活干细胞分裂，这同样为对抗皮肤癌症提供了一个可行的靶点。