Surgical injury and the Wnt pathway

手术损伤和 Wnt 通路

• 批准号: 6572038
• 负责人: FRANK ISIK
• 金额: $ 33.68万
• 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/6572038
• 关键词: angiogenesis; apoptosis; biological signal transduction; bone marrow; cadherins; calcium ion; cell differentiation; cell proliferation; cell type; developmental genetics; epithelium; flow cytometry; gene expression; genetically modified animals; green fluorescent proteins; histogenesis; immunocytochemistry; in situ hybridization; laboratory mouse; protein kinase C; protein signal sequence; protein structure function; regeneration; skin; transfection /expression vector; wound healing

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(申请人提供)：伤口修复涉及多种细胞事件的协调，包括终末分化的固有细胞的增殖和迁移，如角质形成细胞、成纤维细胞和内皮细胞。在成人皮肤中，伤口愈合重建了适应的上皮，没有表皮附属物，并产生了不同的富含胶原蛋白的收缩真皮。根本的问题是，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。皮肤和骨髓分别含有未分化上皮细胞和间充质细胞类型，可为皮肤损伤提供再生细胞成分。我们的初步数据显示，骨髓来源的细胞确实存在于愈合的伤口中，提供上皮细胞和真皮细胞类型。这些观察结果必须进一步评估，以确定可能调节皮肤和创面中骨髓来源细胞命运的分化信号(S)。未分化的细胞对形态原做出反应，形态原是决定细胞命运的信号蛋白家族。在这些家族中，Wnt基因是决定细胞发育过程中命运的关键影响因子，并通过两条途径激活基因转录，一条依赖于游离b-catenin的积累(Wnt/b-catenin途径)，另一条依赖于细胞内钙离子和蛋白激酶C(Wnt/Ca2+途径)。我们的初步数据显示，Wnt基因在体内具有明显的创伤后再生效应。我们建议确定骨髓来源的细胞和Wnt基因在成人皮肤创伤修复中的作用。我们的假设是，在创伤修复形态发生过程中，Wnt/b-catenin途径调控表皮细胞命运和表皮再生，Wnt/Ca~(2+)通路调控间充质细胞命运和真皮再生。我们将通过以下具体目标来验证我们的假设：1.确定骨髓来源的细胞在伤口修复和再生中的作用。2.确定Wnt信号是否调节BM来源细胞和创伤驻留细胞的分化。3.确定激活或阻断Wnt通路是否改变了伤口的修复和再生。