Surgical injury and the Wnt pathway

手术损伤和 Wnt 通路

• 批准号: 6990597
• 负责人: FRANK ISIK
• 金额: $ 30.64万
• 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/6990597
• 关键词: Surgical; injury; Wnt; pathway

DESCRIPTION (provided by applicant): 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 b-catenin (Wnt/ b-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/ b-catenin pathway regulates epidermal cell fate and epidermal regeneration and the Wnt/ Ca2+ 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.

描述（由申请人提供）：伤口修复涉及多种细胞事件的协调，包括终末分化的本土细胞的增殖和迁移，例如角质形成细胞、成纤维细胞和内皮细胞。在成人皮肤中，伤口愈合会重建缺乏表皮附属物的适应上皮，并产生不同程度富含胶原蛋白的收缩真皮。根本问题是成人皮肤伤口是通过修复而不是再生来愈合的。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，可以提供再生细胞成分以应对皮肤损伤。我们的初步数据表明，骨髓来源的细胞确实会填充正在愈合的伤口，以提供上皮细胞和真皮细胞类型。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骨髓衍生细胞命运的分化信号。未分化细胞对形态发生素做出反应，形态发生素是决定细胞命运的信号蛋白家族。其中一个家族 Wnt 基因是发育过程中细胞命运决定的关键效应器，并通过两种途径激活基因转录，一种依赖于游离 b-连环蛋白（Wnt/b-连环蛋白途径）的积累，另一种依赖于细胞内 Ca2+ 和蛋白激酶 C（Wnt/Ca2+ 途径）。我们的初步数据表明Wnt基因在受伤后体内具有显着的再生作用。我们建议确定 BM 衍生细胞和 Wnt 基因在成人皮肤伤口修复中的作用。我们的假设是，在伤口修复形态发生过程中，Wnt/b-连环蛋白途径调节表皮细胞命运和表皮再生，Wnt/Ca2+途径调节间充质细胞命运和真皮再生。我们将通过以下具体目标来检验我们的假设： 1. 确定骨髓来源细胞对伤口修复和再生的贡献。 2. 确定Wnt信号传导是否调节骨髓源性细胞和伤口常驻细胞的分化。 3. 确定激活或阻断Wnt通路是否会改变伤口修复和再生。