Surgical injury and the Wnt pathway

手术损伤和 Wnt 通路

• 批准号: 6829655
• 负责人: FRANK ISIK
• 金额: $ 31.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829655
• 关键词: Surgical; injury; Wnt; pathway

EXCEED THE SPACE PROVIDED. Wound repair involves the orchestration of multiple cellular events, including the proliferation and migration of terminally differentiated indigenous cells, such as keratinocytes, fibroblasts and endothelial cells. In adult skin, wound healing recreates an adapted epithelium that lacks epidermal appendages and generates a variably collagen-rich, contracted dermis. The underlying problem is that adult cutaneous wounds heal by repair, rather than by regeneration. Methods to promote adult cutaneous tissue regeneration are needed. The skin and bone marrow (BM) harbor undifferentiated epithelial and mesenchymal cell types, respectively that could provide the regenerative cellular components in response to cutaneous injury. Our preliminary data show that BM derived cells do populate the healing wound to provide epithelial and dermal cell types. These observations must be further evaluated to determine the differentiation signal(s) that may regulate the fate of skin and BM-derived cells in the wound. Undifferentiated cells respond to morphogens, which are families of signaling proteins that determine cell fate. One of these families, the Wnt genes, are crucial effectors of cell fate determination during development and activate gene transcription by two pathways, one that is dependent on the accumulation of free _-catenin (Wnt/_-catenin pathway) and the other that is dependent on intracellular Ca2+ and Protein Kinase C (Wnt/Ca2+ pathway). Our preliminary data shows that Wnt genes have marked regenerative effects in vivo following wounding. We propose to determine the roles of BM-derived cells and Wnt genes in adult cutaneous wound repair. Our hypotheses are that during wound repair morphogenesis, the Wnt/13-catenin pathway regulates epidermal cell fate and epidermal regeneration and, the WnVCa2¿ pathway regulates mesenchymal cell fate and dermal regeneration. We will test our hypotheses with the following specific aims: 1. To determine the contribution of bone marrow-derived cells to wound repair and regeneration. 2. To determine whether Wnt signaling regulates differentiation of BM-derived and wound resident cells. 3. To determine whether activating or blocking the Wnt pathways alters wound repair and regeneration. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。伤口修复涉及多种细胞事件的协调，包括终末分化的固有细胞（例如角质形成细胞、成纤维细胞和内皮细胞）的增殖和迁移。在成人皮肤中，伤口愈合重建了缺乏表皮附属物的适应性上皮，并产生了富含胶原蛋白的收缩的真皮。潜在的问题是成人皮肤伤口通过修复而不是再生来愈合。需要促进成人皮肤组织再生的方法。皮肤和骨髓（BM）分别含有未分化的上皮细胞和间充质细胞类型，它们可以提供响应皮肤损伤的再生细胞组分。我们的初步数据表明，骨髓来源的细胞确实填充愈合的伤口，以提供上皮和真皮细胞类型。必须进一步评估这些观察结果，以确定可能调节伤口中皮肤和BM衍生细胞命运的分化信号。未分化的细胞对形态发生素有反应，形态发生素是决定细胞命运的信号蛋白家族。Wnt基因是发育过程中决定细胞命运的重要效应子，通过两条途径激活基因转录，一条依赖于游离β-catenin的积累（Wnt/β-catenin途径），另一条依赖于细胞内Ca~（2+）和蛋白激酶C（Wnt/Ca~（2+）途径）。我们的初步数据表明，Wnt基因在体内创伤后具有显著的再生作用。我们建议确定BM衍生细胞和Wnt基因在成人皮肤创伤修复中的作用。我们的假设是，在伤口修复形态发生过程中，Wnt/13-catenin途径调节表皮细胞命运和表皮再生，WnVCa 2 <$途径调节间充质细胞命运和真皮再生。我们将测试我们的假设与以下具体目标：1。确定骨髓源性细胞对创伤修复和再生的贡献。2.确定Wnt信号传导是否调节BM衍生细胞和伤口驻留细胞的分化。3.确定激活或阻断Wnt通路是否会改变伤口修复和再生。性能现场=