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: 8225295
• 负责人: Peter J. Koch
• 金额: $ 37.44万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225295
• 关键词: Adhesives; Affect; 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; 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; desmocollin; desmoglein; in vivo; keratinocyte; mammary gland development; 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（由申请人提供）：脱糖体是高度动态的细胞 - 细胞粘附复合物，具有调节其粘附性能和分子组成的能力，从而影响细胞迁移，细胞分类和细胞分化。实现这一目标的一种机制是将脱骨钙蛋白[desmocollins（dsc）和desmogleins（DSG）（DSG）]的比率变化，这些机制被组装成朝底。关于在皮肤和皮肤附属物发育过程中控制脱骨功能的基因调节途径知之甚少。本应用的目的是确定在皮肤附属物（例如毛囊，乳腺）发育过程中如何调节DSC基因的表达。我们已经从Wnt，NFKB和Notch信号传导途径中鉴定了转录因子，这些途径差异地调节了培养细胞中的DSC基因。为了检验我们的假设，即这些转录因子还控制着培养的角质形成细胞中的DSC基因表达以及在发育皮肤附属物中，我们提出了以下特定目的：1。）分析主要信号转导途径对体外表达体外表达的影响。 2.）确定WNT信号在发育过程中对DSC2和DSC3基因表达的影响。 3.）使用体内互补测定法确定体内DSC3功能是否需要Wnt信号。该项目的结果将使人们更好地了解形态发生过程（例如附属物形成）在开发过程中如何受到调节。此外，了解脱染色体基因的调节将有助于开发新的概念，从而在载被和遗传性疾病的治疗中受到脱骨功能受损引起的疾病。项目叙述：该项目的目的是确定在哺乳动物发育过程中控制脱骨功能的基因调节途径，特别是控制皮肤及其附属形成的途径（例如毛囊，乳腺）。

项目成果

Modeling AEC-New approaches to study rare genetic disorders.

• DOI: 10.1002/ajmg.a.36455
• 发表时间: 2014-10
• 期刊: American journal of medical genetics. Part A
• 作者: Koch PJ;Dinella J;Fete M;Siegfried EC;Koster MI
• 通讯作者: Koster MI

Plakoglobin as a regulator of desmocollin gene expression.

• DOI: 10.1038/jid.2013.220
• 发表时间: 2013-12
• 期刊: JOURNAL OF INVESTIGATIVE DERMATOLOGY
• 影响因子: 6.5
• 作者: Tokonzaba, Etienne;Chen, Jiangli;Cheng, Xing;Den, Zhining;Ganeshan, Radhika;Muller, Eliane J.;Koch, Peter J.
• 通讯作者: Koch, Peter J.

Desmosomal defects in acantholytic squamous cell carcinomas.

• DOI: 10.1111/cup.12390
• 发表时间: 2014-11
• 期刊: Journal of cutaneous pathology
• 影响因子: 1.7
• 作者: O'Shea C;Fitzpatrick JE;Koch PJ
• 通讯作者: Koch PJ