DESMOSOMES--ASSEMBLY AND ROLE IN EPIDERMAL MORPHOGENESIS

描述(改编自申请者摘要)：桥粒是一种 细胞连接的关键类型--细胞骨架复合体。跨膜 桥粒糖蛋白包括桥粒(DSC)和桥粒糖蛋白 (DSG)，这两个成员的钙粘附素家族的细胞黏附分子。这个 这些分子的胞外部分被认为是细胞-细胞之间的中介 相互作用，细胞内区域作为锚定位置 中间细丝。表皮完整性丧失，起水泡 形成是由针对桥粒蛋白的自身抗体引起的。 叶状天疱疮和寻常型天疱疮。申请人的前科 研究表明，白蛋白(PG)与 桥粒钙粘附素的胞内结构域是关键的 桥粒组装的步骤。在初步研究中发现， 白蛋白与钙粘附素有三个不同的结合部位。 结合专一性。有人建议进行研究，以检验这一假设 白蛋白可能通过偶联多个钙粘附素并调节其功能发挥作用 与一些未知的质膜蛋白相互作用。为了测试 这一假设、缺失突变体和定点突变将被使用 为了表征PG和钙粘附素的分子决定因素， 对他们的互动负责。将使用类似的方法来 研究PG对桥粒的靶向性。磷酸化在细胞周期调控中的作用 对这些过程的监管也将得到确定。此外， 我们将研究桥粒断裂对细胞-细胞黏附的影响。 利用HaCaT细胞的体外皮肤等效性。

DESCRIPTION (Adapted from the applicant's Abstract): The desmosome is one of the key types of the cell junction-cytoskeleton complexes. Transmembrane desmosomal glycoproteins include the desmocollins (Dsc) and desmogleins (Dsg), both members of the cadherin family of cell adhesion molecules. The extracellular portion of these molecules are thought to mediate cell-cell interactions, and the intracellular region serves as an anchoring site for intermediate filaments. Loss of the epidermal integrity and blister formation is caused by autoantibodies directed against the desmogleins in pemphigus foliaceous and pemphigus vulgaris. The applicant's previous studies have led to the proposal that plakoglobin's (Pg) association with the intracellular domain of the desmosomal cadherins is one of the critical steps in desmosome assembly. In preliminary studies, it has been found that plakoglobin has three binding sites for cadherins that differ in their binding specificity. Studies are proposed to test the hypothesis that plakoglobin may function by coupling several cadherins and mediating their interaction with some unknown plasma membrane protein. In order to test this hypothesis, deletion mutants and site directed mutagenesis will be used to characterize the molecular determinants of Pg and the cadherins that are responsible for their interactions. A similar approach will be used to study the targeting of Pg to the desmosome. The role of phosphorylation in the regulation of these processes will also be determined. In addition, the effect of desmosome disruption on cell-cell adhesion will be studied in an in vitro skin equivalent utilizing HaCaT cells.