Epithelial Stem Cell Migration during Wound Repair

伤口修复过程中上皮干细胞的迁移

• 批准号: 8061143
• 负责人: Catherine Pei-Ju Lu
• 金额: $ 5.13万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061143
• 关键词: Accounting; Address; Adult; Area; Behavior; Binding; Bioinformatics; Biological Assay; Cell Adhesion Molecules; Cell Proliferation; Cell Surface Receptors; Cells; Data; Dehydration; Embryo; Engraftment; Epidermis; Epithelial; Equilibrium; Exhibits; Extracellular Matrix; Focal Adhesion Kinase 1; Gene Expression; Generations; Genes; Genetic Transcription; Growth Factor; Hair follicle structure; Homeostasis; Image; Immigration; Immunohistochemistry; In Situ Hybridization; In Vitro; Injury; Integrins; Knowledge; Left; Methods; Molecular; Molecular Profiling; Monitor; Mus; Natural regeneration; Neoplasm Metastasis; Pattern; Physiological; Play; Population; Process; Regenerative Medicine; Relative (related person); Research; Research Proposals; Rest; Role; Sebaceous Glands; Signal Pathway; Signal Transduction; Site; Skin; Stem cells; Stratum Basale; Structure; Structure of infundibulum of hair follicle; Testing; Time; Tissues; Transgenic Mice; Wild Type Mouse; Wound Healing; cancer stem cell; cell motility; comparative; design; genome-wide; in vivo; insight; keratinocyte differentiation; knock-down; migration; mouse model; novel; pathogen; prevent; repaired; research study; response; response to injury; self-renewal; small hairpin RNA; stem cell population; tumor; tumor progression; wound

DESCRIPTION (provided by applicant): Upon injury, the skin epidermis must undergo immediate repair mechanism to restore its barrier function to prevent dehydration and invasion of harmful pathogens. Wound repair of the skin epidermis involves activation, migration, proliferation, and differentiation of keratinocytes. In particular, the re-epithelialization of the wounded area requires skin epithelial stem cells, which migrate in both from the surrounding epidermis and also from the hair follicle. However, very little is known about the signals that activate stem cell migration and the molecular mechanisms directing their migration during wound repair. How do hair follicle stem cells respond to wound signals? What are the signaling pathways that direct stem cell migration during wound repair? Which population(s) of epithelial stem cells is responsible for repairing the epidermis and generation of new hair follicles? In this research plan, I propose to: (1) Identify the cells within the hair follicle that contribute to wound repair; (2) Purify and characterize the cells within the hair follicle that contribute to wound repair; (3) Monitor and characterize cells as they migrate during wound repair; and (4) Perform functional studies on molecules that may be involved in cell migration and re-epithelialization during wound repair. I plan to exploit mouse models that allow lineage tracing of skin stem cells and their progeny during the process of wound healing. This enables characterization and isolation of skin stem cells that contribute to wound repair and generation of new hair follicles. A genome-wide gene profiling will be conducted to examine the changes in gene expression, and to identify molecules and signal pathways that may be involved in migration of the skin stem cells. I will perform further functional assays to validate the participation of the candidate molecules in the migration process. Findings from this research plan will contribute to our understanding of the molecular mechanism of skin stem cell migration upon injury and provide answers to many fundamental questions in the stem cell field. PUBLIC HEALTH RELEVANCE: The main focus of this research proposal is to understand the molecular mechanisms involved in the activation and migration of epithelial stem cells during wound repair and to study the population(s) of stem cells in the hair follicles that may contribute to epidermis regeneration and new hair follicle formation at the wound sites. Since the molecular interactions between tumor and its microenvironment are similar to a wounding situation in many aspects, it is plausible to hypothesize that many of the same signals mobilizing skin stem cells to leave their original niche upon wounding may as well mobilize cancer stem cells and cause tumor metastasis. Thus, this proposed research is likely to provide insights on mechanisms of cancer progression, and the knowledge acquired from this research plan will advance our current understanding of how tissues heal wounds, as well as have implications for regenerative medicine.

描述（由申请人提供）：受伤后，皮肤表皮必须立即进行修复机制，以恢复其障碍功能，以防止有害病原体的脱水和侵袭。皮肤表皮的伤口修复涉及角质形成细胞的激活，迁移，增殖和分化。特别是，受伤区域的再上皮化需要皮肤上皮干细胞，这些干细胞在周围的表皮和毛囊中都迁移。但是，关于激活干细胞迁移以及指导其在伤口修复期间迁移的分子机制的信号知之甚少。毛囊干细胞如何应对伤口信号？在伤口修复过程中，直接干细胞迁移的信号通路是什么？哪些上皮干细胞的种群负责修复表皮和新毛囊的产生？在本研究计划中，我建议：（1）确定毛囊中有助于伤口修复的细胞； （2）纯化并表征毛囊中有助于伤口修复的细胞； （3）监测和表征细胞在伤口修复过程中迁移时的细胞； （4）对可能参与细胞迁移和伤口修复期间重新上皮化的分子进行功能研究。我计划利用小鼠模型，以允许在伤口愈合过程中对皮肤干细胞及其后代进行谱系追踪。这使皮肤干细胞的表征和隔离有助于伤口修复和新毛囊的产生。将进行全基因组基因分析，以检查基因表达的变化，并鉴定可能与皮肤干细胞迁移有关的分子和信号途径。我将执行进一步的功能测定，以验证候选分子在迁移过程中的参与。该研究计划的发现将有助于我们对损伤后皮肤干细胞迁移的分子机制的理解，并为干细胞场中许多基本问题提供答案。 公共卫生相关性：这项研究建议的主要重点是了解伤口修复过程中上皮干细胞激活和迁移的分子机制，并研究毛囊中干细胞的种群，这可能导致表皮再生和伤口部位的新毛卵泡形成。由于在许多方面，肿瘤与其微环境之间的分子相互作用类似于受伤的情况，因此可以假设许多相同的信号动员皮肤干细胞在受伤后离开其原始生态裂，也可能动员癌症干细胞并引起肿瘤转移。因此，这项拟议的研究可能会提供对癌症进展机制的见解，从该研究计划中获得的知识将提高我们目前对组织如何治愈伤口的理解，以及对再生医学的影响。