Mechanisms of Ctip2-regulated contribution of hair stem cells to skin wounds

 描述(由申请人提供)：延迟或损害皮肤伤口愈合，尤其是糖尿病、烧伤伤口、腿部溃疡和压疮，给美国和世界各地的患者和卫生保健专业人员带来了巨大的挑战。每年在伤口护理上花费数十亿美元，使人类皮肤创伤对公共卫生和整体经济构成越来越大的威胁。毛囊干细胞(HFSC)的壁龛有助于伤口愈合过程，Krt15标记了毛囊干细胞室。然而，HFSC在创面修复过程中的募集机制及其在创面愈合不同阶段的作用尚不清楚。此外，控制干细胞在毛囊室中迁移的因素也不是全部确定。因此，了解转录因子在不同的HFSC生态位中表达的作用，并调控皮肤创伤愈合过程中的基因表达，以寻找促进人类患者创伤愈合的新的治疗靶点，是一个尚未得到满足的需求。转录因子Ctip2在表皮动态平衡和屏障形成以及皮肤创面愈合过程中发挥重要作用。R15建议的目的是阐明Ctip2+|Krt15+干细胞对伤口愈合的贡献，并确定这些贡献的机制基础。这一目标将在中心假设的背景下完成：Ctip2调节HFSC间隔室中基因网络的表达，该网络中Ctip2的转录靶点通过动员干细胞和促进再上皮化和/或细胞迁移来影响皮肤伤口的愈合。本项目的目标是通过谱系追踪研究(目标1)确定Ctip2+HFSC对皮肤伤口愈合的贡献(目标1)，并通过在不同部位构建Ctip2调节的基因网络(目标2)来确定促进伤口愈合的新的治疗靶点。完成这项研究应该：明确由Ctip2控制的直接影响伤口愈合的遗传和调控网络；并培训学生掌握21世纪的生物医学研究技术。这些研究将对再生医学在糖尿病、慢性、慢愈合伤口的皮肤伤口修复中的应用产生影响，并将对人类健康产生重大而积极的影响。从拟议的研究中获得的知识可能有助于通过修复皮肤附属物来修复人类的皮肤伤口，这目前是不可能的。

 DESCRIPTION (provided by applicant): Delayed or compromised cutaneous wound healing, particularly in diabetes, burn wounds, leg ulcers and pressure ulcers, presents significant challenges to patients and health care professional in US and worldwide. Billions of dollars spent on wound care every year, making human skin wounds a growing threat to the public health and overall economy. Hair follicle stem cell (HFSC) niches contribute to wound healing processes and Krt15 labels the hair bulge stem cell compartment. However, the mechanisms of recruitment of HFSC during wound repair and their contribution at different stages of wound healing are not well understood. Also, the factors controlling the migration of stem cells in the hair follicle compartments are not all identified. Thus, there is an unmet need to understand the role of transcription factors expressed in the different HFSC niches and regulate gene expression during cutaneous wound healing, to identify new therapeutic targets for accelerating wound healing in human patients. Transcription factor Ctip2 plays essential roles in epidermal homeostasis and barrier formation, and in cutaneous wound healing. The objective of this R15 proposal is to elucidate contributions of Ctip2+|Krt15+ stem cells to wound healing and determine the mechanistic basis for these contributions. The objective will be accomplished in the context of the central hypothesis: Ctip2 regulates expression of a gene network in HFSC compartments, and the transcriptional targets of Ctip2 within this network impact cutaneous wound healing by mobilizing stem cells and enhancing re-epithelialization and/or cellular migration. The goals of this project are to determine the contribution of Ctip2+ HFSC to cutaneous wound healing by lineage-tracing studies (Aim 1) and to identify new therapeutic targets toward accelerating wound healing by constructing Ctip2-regulated gene networks in different HFSC compartments (Aim 2). Completing this research should have: defined Ctip2-controlled genetic and regulatory networks, which directly impact wound healing; and trained students in 21st century biomedical research techniques. These studies will have implications for regenerative medicine in skin wound repair of diabetic, chronic, slow-healing wounds and will have a significant and positive impact on human health. Knowledge gained from the proposed studies may help in the healing of skin wounds in humans via restoration of the skin appendages, currently not possible.