Desmosomal components and epithelial cell fate decision

桥粒成分与上皮细胞命运决定

基本信息

批准号：
7494106
负责人：
My Georgia Mahoney
金额：
$ 16.33万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-07 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7494106
关键词：
1-Phosphatidylinositol 3-Kinase Adherens Junction Adhesions Adhesives Affect Anoikis Apoptosis Architecture Autoimmune Process Cadherins Cell Adhesion Molecules Cell Proliferation Cell Survival Cell-Cell Adhesion Complex Condition Depth Desmosomes Development Disease Ectopic Expression Elements Embryonic Development Epidermis Epithelial Epithelial Cells Epithelium Exhibits Genes Goals Growth and Development function Hair Hair follicle structure Health Human In Vitro Inherited Intercellular Junctions Investigation Knockout Mice Lesion Light Link MEKs Malignant - descriptor Malignant Neoplasms Mediating Microarray Analysis Molecular Mus Neoplasm Metastasis Papilloma Pathway interactions Personal Satisfaction Phenotype Play Predisposition Premalignant Protein Overexpression Proteins Public Health Applications Research Resistance Role Signal Pathway Signal Transduction Signal Transduction Pathway Skin Squamous cell carcinoma Stem cells Structure Supporting Cell Tissues Transgenic Mice Transgenic Organisms Tumor Biology Up-Regulation base cancer therapy carcinogenesis cell growth chemical carcinogen desmoglein desmoglein 2 in vivo keratinocyte malignant phenotype mouse model novel therapeutic target tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Desmosomes are intercellular adhesive junctions that play pivotal roles in maintaining tissue architecture and function as illustrated by the development of several skin fragility and hair abnormality conditions when they are impaired. Desmogleins (Dsg) are the Ca2+dependent adhesion components of desmosomes and Dsg1, 3, and 4 are the target molecules in several human autoimmune, infectious, and inherited diseases. Thus, the roles of these proteins in cell-cell adhesion, skin barrier function, and hair follicle development are well established. However, whether these desmogleins can mediate intracellular signal transduction pathways is poorly understood. Studies of Dsg2 null mice attest to the importance of Dsg2 during embryonic development and in stem cell growth and survival. Furthermore, Dsg2 is overexpressed in certain epithelial malignancies including squamous cell carcinomas (SCC) suggesting its role in cell proliferation and differentiation that favor of tumor development. However, it is unknown whether - and if so how - Dsg2 contributes to the malignant phenotype of SCC. Consequently we established an in vivo transgenic mouse model overexpressing Dsg2 in the epidermis. Preliminary results demonstrate that ectopic expression of Dsg2 induced a hyperproliferative epidermal phenotype, increased apoptosis resistance of keratinocytes, and enhanced development of papillomas. Consistent with these observations, Dsg2 overexpression was also associated with deregulated epidermal signal transduction and upregulation of tumor-associated genes including the metastasis-associated proteins. These signaling components have previously been implicated in hyperproliferation and/or malignant transformation of epithelial cells and tissues. Based on this strong preliminary evidence we propose to molecularly define the pathways by which Dsg2 modulates epithelial cell fate. This goal will be pursued in two specific aims to: 1) determine the molecular mechanisms by which Dsg2 expression supports epithelial cell survival and proliferation, and 2) determine molecular mechanisms underlying increased susceptibility of Dsg2 Tg mice to skin tumorigenesis in vivo. Overall, the proposed studies will elucidate novel intracellular signaling roles of Dsg2 as they relate to skin structure, function, and carcinogenesis. Project Narrative/Relevance to Public Health: This application will help define the roles of desmosomal cadherins in modulating, not only epithelial cell-cell adhesion, but also cell growth and survival. In particular, we will focus on desmoglein 2, which is up regulated in several epithelia-derived cancers. Determining the molecular mechanisms by which desmoglein 2 affects tumor growth and development has the potential of identifying new targets for therapeutic cancer treatments.

描述（由申请人提供）：桥粒是细胞间粘附连接，在维持组织结构和功能方面发挥着关键作用，如多种皮肤脆弱性和毛发异常状况在受损时的发展所示。桥粒糖蛋白 (Dsg) 是桥粒的 Ca2+ 依赖性粘附成分，Dsg1、3 和 4 是多种人类自身免疫性疾病、感染性疾病和遗传性疾病的靶分子。因此，这些蛋白质在细胞间粘附、皮肤屏障功能和毛囊发育中的作用已得到充分证实。然而，这些桥粒芯糖蛋白是否可以介导细胞内信号转导途径尚不清楚。对 Dsg2 缺失小鼠的研究证明了 Dsg2 在胚胎发育以及干细胞生长和存活过程中的重要性。此外，Dsg2 在某些上皮恶性肿瘤中过度表达，包括鳞状细胞癌 (SCC)，表明它在有利于肿瘤发展的细胞增殖和分化中发挥作用。然而，尚不清楚 Dsg2 是否（如果是的话）如何导致鳞状细胞癌的恶性表型。因此，我们建立了表皮中过度表达 Dsg2 的体内转基因小鼠模型。初步结果表明，Dsg2 的异位表达诱导表皮过度增殖表型，增加角质形成细胞的凋亡抗性，并促进乳头状瘤的发展。与这些观察结果一致，Dsg2 过度表达也与表皮信号转导失调和肿瘤相关基因（包括转移相关蛋白）的上调有关。这些信号传导成分先前已被认为与上皮细胞和组织的过度增殖和/或恶性转化有关。基于这一强有力的初步证据，我们建议从分子水平上定义 Dsg2 调节上皮细胞命运的途径。该目标将通过两个具体目标来实现：1）确定Dsg2表达支持上皮细胞存活和增殖的分子机制，2）确定Dsg2 Tg小鼠体内皮肤肿瘤发生易感性增加的分子机制。总体而言，拟议的研究将阐明 Dsg2 的新细胞内信号传导作用，因为它们与皮肤结构、功能和致癌作用有关。项目叙述/与公共卫生的相关性：该应用将有助于确定桥粒钙粘蛋白在调节上皮细胞-细胞粘附以及细胞生长和存活中的作用。我们特别关注桥粒芯糖蛋白 2，它在几种上皮源性癌症中表达上调。确定桥粒芯糖蛋白 2 影响肿瘤生长和发育的分子机制有可能确定癌症治疗的新靶点。