DESMOSOMES--ASSEMBLY AND ROLE IN EPIDERMAL MORPHOGENESIS

描述（改编自申请人的摘要）：桥粒是一种 细胞连接-细胞骨架复合物的关键类型。 跨膜 桥粒糖蛋白包括桥粒柯林斯（Dsc）和桥粒糖蛋白 (Dsg)两者都是细胞粘附分子的钙粘蛋白家族的成员。 的 这些分子的细胞外部分被认为介导细胞-细胞 相互作用，细胞内区域作为锚定位点， 中间丝 表皮完整性丧失和水疱 形成是由针对桥粒芯糖蛋白的自身抗体引起的， 落叶型天疱疮和寻常型天疱疮。 申请人以前的 研究表明，斑珠蛋白（Pg）与 桥粒钙粘蛋白的胞内区域是 桥粒组装的步骤。 初步研究发现， 斑珠蛋白有三个钙粘蛋白结合位点，这些位点的结合方式不同 结合特异性 有人提出研究来检验这一假设， 斑珠蛋白可能通过偶联几种钙粘蛋白并介导它们的 与一些未知质膜蛋白相互作用。 为了测试 将使用该假设、缺失突变体和定点诱变 为了表征Pg和钙粘蛋白的分子决定因素， 负责他们的互动。 类似的方法将用于 研究Pg对桥粒的靶向性。 磷酸化在 还将确定对这些进程的管理。 此外该 桥粒破坏对细胞-细胞粘附的影响将在一个 利用HaCaT细胞的体外皮肤等同物。

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.