Cross-talk Between Desmosomal Proteins and Signaling Pathways in the Skin

桥粒蛋白与皮肤信号通路之间的串扰

• 批准号: 7372074
• 负责人: Peter J. Koch
• 金额: $ 32.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372074
• 关键词: Adhesives; Affect; Appendix; Architecture; Binding; Binding Sites; Biological; Biological Assay; Biological Process; Cadherins; Cardiomyopathies; Cell Adhesion; Cell Differentiation process; Cell Separation; Cell-Cell Adhesion; Complex; Cultured Cells; Data; Dermis; Desmosomes; Development; Disease; Dissection; Embryo; Epithelial Cells; Epithelium; Extracellular Domain; Gene Expression; Gene Family; Genes; Goals; Green Fluorescent Proteins; Growth; Hair follicle structure; Homeostasis; Human; In Vitro; Inherited; Invaded; Knockout Mice; LacZ Genes; Lead; Mammary gland; Mediating; Molecular; Monitor; Mus; Mutation; Notch Signaling Pathway; Organ; Pathway interactions; Pattern; Phenotype; Process; Property; Protein Isoforms; Proteins; Regulation; Regulatory Pathway; Reporter; Repression; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Skin; Sorting - Cell Movement; System; Testing; Transgenes; Ventricular; appendage; armadillo proteins; base; cell motility; concept; desmocollin; desmoglein; in vivo; keratinocyte; migration; mouse genome; notch protein; null mutation; plakoglobin; promoter; transcription factor

DESCRIPTION (provided by applicant): Desmosomes are highly dynamic cell-cell adhesion complexes that have the ability to adjust their adhesive properties and molecular composition, thereby affecting cell migration, cell sorting and cell differentiation. One mechanism by which this is achieved is a change in the ratio of desmosomal cadherins [desmocollins (Dsc) and desmogleins (Dsg)] that are assembled into the desmosome. Very little is known about the gene regulatory pathways that control desmosome function during skin and skin appendage development. The goal of the present application is to determine how the expression of the Dsc genes is regulated during skin appendage (e.g. hair follicles, mammary gland) development. We have already identified transcription factors from the Wnt, NFkB and Notch signaling pathways that differentially regulate Dsc genes in cultured cells. To test our hypothesis that these transcription factors also control Dsc gene expression in cultured keratinocytes and in developing skin appendages, we propose the following specific aims: 1.) To analyze the effects of major signal transduction pathways on the expression of desmocollins in vitro. 2.) To determine the effects of Wnt Signaling on Dsc2 and Dsc3 gene expression during development. 3.) To use an in vivo complementation assay to determine whether Wnt signaling is required for Dsc3 function in vivo. The results of this project will lead to a better understanding of how morphogenetic processes, such as appendage formation, are regulated during development. Furthermore, understanding the regulation of desmosomal genes will help to develop new concepts in the therapy of acquired and inherited diseases caused by impaired desmosome function. Project Narrative: The goal of this project is to identify gene regulatory pathways that control desmosome function during mammalian development, in particular pathways that control the formation of the skin and its appendages (e.g. hair follicles, mammary glands).

描述（申请人提供）：桥粒是高度动态的细胞-细胞粘附复合物，能够调节其粘附特性和分子组成，从而影响细胞迁移、细胞分选和细胞分化。实现这一目标的机制之一是组装到桥粒中的桥粒钙粘蛋白 [桥粒胶蛋白 (Dsc) 和桥粒糖蛋白 (Dsg)] 的比例发生变化。对于皮肤和皮肤附属器发育过程中控制桥粒功能的基因调控途径知之甚少。本申请的目的是确定Dsc基因的表达在皮肤附属器（例如毛囊、乳腺）发育过程中是如何受到调节的。我们已经从 Wnt、NFkB 和 Notch 信号通路中鉴定出转录因子，这些转录因子可差异调节培养细胞中的 Dsc 基因。为了检验我们的假设，即这些转录因子也控制培养的角质形成细胞和发育中的皮肤附属器中的 Dsc 基因表达，我们提出以下具体目标：1.) 分析主要信号转导途径对体外桥粒胶蛋白表达的影响。 2.) 确定 Wnt 信号转导对发育过程中 Dsc2 和 Dsc3 基因表达的影响。 3.) 使用体内互补测定来确定 Dsc3 体内功能是否需要 Wnt 信号传导。该项目的结果将有助于更好地理解形态发生过程（例如附属物形成）在发育过程中是如何受到调节的。此外，了解桥粒基因的调控将有助于开发治疗由桥粒功能受损引起的获得性和遗传性疾病的新概念。项目叙述：该项目的目标是确定在哺乳动物发育过程中控制桥粒功能的基因调控途径，特别是控制皮肤及其附属物（例如毛囊、乳腺）形成的途径。