COBRE: UNE MED CTR: P1: ROLE OF DESMOSOMES IN ORAL SQUAMOUS CELL CARCINOMA

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。桥粒是复层鳞状上皮组织中突出的细胞-细胞连接，其组成在组织的不同层的细胞之间变化。尚不清楚为什么细胞利用不同的组分在同一组织内组装桥粒。然而，很可能由不同分子组分组成的桥粒执行不同的功能并导致改变的粘附特性。桥粒蛋白的表达通常在鳞状细胞癌中减少，然而，这些蛋白对肿瘤发生的贡献在很大程度上是未知的。我们的长期目标是了解桥粒在维持鳞状上皮组织正常表型中的作用，并确定它们在肿瘤发生过程中的改变是否影响细胞行为。我们的假设是桥粒组成的变化导致差异粘附和/或改变细胞-细胞信号传导。我们的实验室在细胞-细胞粘附和细胞运动的功能分析方面有着丰富的经验，我们的定位是为我们理解桥粒功能和这种细胞结构在鳞状细胞癌发展中的作用做出重大贡献。具体目标是：1）确定桥粒的组成是否影响细胞的粘附、增殖和运动;和2）进一步了解plakophilin-1在桥粒和细胞核中的功能。Plakophilin-1是一种桥粒蛋白，存在于细胞核和质膜中，这使我们提出Plakophilin-1参与可能与桥粒粘附有关的核信号传导。我们将使用结构/功能研究来研究plakophilin-1的核质转运机制;使用plakophilin-1的独特的“可活化”形式来研究这种蛋白在粘附和细胞信号传导中的作用;并研究与plakophilin-1相关的核蛋白。总的来说，本文提出的研究将定义桥粒组分对细胞运动性、侵袭性和信号传导的贡献。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Desmosomes are prominent cell-cell junctions in stratified squamous epithelial tissues, whose composition varies among cells of the different layers of the tissue. It is not known why cells utilize different components to assemble desmosomes within the same tissue. However, it is likely that desmosomes comprised of different molecular components perform diverse functions and lead to altered adhesive characteristics. Desmosomal protein expression is generally reduced in squamous cell carcinomas; however, the contribution of these proteins to tumorigenesis is largely unknown. Our long-term goals are to understand the role desmosomes play in maintaining the normal phenotype of squamous epithelial tissues and to determine if their alteration during tumorigenesis influences cellular behavior. Our hypothesis is that changes in desmosomal composition result in differential adhesion and/or altered cell-cell signaling. Our laboratory has extensive experience in functional analysis of cell-cell adhesion and cell motility, and we are positioned to make significant contributions to our understanding of desmosome function and the role this cellular structure plays in the development of squamous cell carcinomas. The specific aims are: 1) To determine if the composition of desmosomes influences cell adhesion, proliferation and motility; and 2) To further understand the function of plakophilin-1 in the desmosome and in the nucleus. Plakophilin-1 is a desmosomal protein that is found in the nucleus as well as in the plasma membrane, which led us to propose that plakophilin-1 participates in nuclear signaling that may be linked to desmosomal adhesion. We will use structure/function studies to investigate the mechanism of nucleo-cytoplasmic transport of plakophilin-1 ; use a unique "activatible" form of plakophilin-1 to investigate the role of this protein in adhesion and in cellular signaling; and investigate nuclear proteins that associate with plakophilin-l. Collectively, the studies proposed herein will define the contribution of desmosomal components to cellular motility, invasiveness and signaling.