Shedding of epidermal transmembrane proteins

人皮肤的基底膜区（BM）是一个上皮-间充质界面，旨在提供粘附和抵抗外部剪切力。特化的超分子蛋白质复合物将表皮附着到真皮，并且对于基底细胞细胞骨架与BM的稳定连接至关重要。在肌肉中，一种非常相似的超分子聚集体，肌营养不良蛋白糖蛋白复合物，将肌细胞内部与BM连接起来。这些复合物的许多蛋白质是已知的，它们的基因缺陷会导致遗传性疾病。肌肉复合体的一种成分肌营养不良蛋白聚糖（DG）最近已被证明也存在于某些上皮细胞中。我们证明了α-和β-DG亚基都存在于皮肤BM中并由体外角质形成细胞合成。在这里，我们提出的DG皮肤亚型的结构，生物合成和调节的分子表征，以及其配体和功能的测定。使用人类皮肤病和转基因小鼠作为模型，DG在遗传性和炎症性皮肤病的致病途径中的作用将被确定。除了扩大我们对BM蛋白的基础生物学的知识，我们希望通过该项目为BM疾病和其他常见医学问题（如伤口愈合）的新治疗策略的开发做出贡献。

The basement membrane zone (BM) in human skin is an epithelial-mesenchymal interface designed to provide adherence and resistance against outer shearing forces. Specialized supramolecular protein complexes attach the epidermis to the dermis and are critical for the stable connection of the basal cell cytoskeleton with the BM. In the muscle, a very similar supramolecular aggregate, the dystrophin glycoprotein complex, links the inside of muscle cells with the BM. A number of proteins of these complexes are known, and defects in their genes lead to hereditary diseases. A component of the muscle complex, dystroglycan (DG), has recently been shown to occur also in certain epithelia. We demonstrated that both a- und ß-DG subunits are present at the skin BM and synthesized by keratinocytes in vitro. Here we propose molecular characterization of the structure, biosynthesis and regulation of the DG skin isoform, as well as the determinations of its ligands and functions. Using human skin diseases and a transgenic mouse as models, the role of DG in the pathogenetic pathways underlying genetic and inflammatory dermatoses will be determined. In addition to expanding our knowledge on the basic biology of BM proteins, we hope to contribute with this project to the development of novel therapeutic strategies for BM diseases and for other, common medical problems such as wound healing.