DESMOCOLLIN 1 IN EPIDERMAL DEVELOPMENT & HOMEOSTASIS

描述：（逐字）--桥粒是细胞粘附结构（连接） 在表皮中特别丰富。这些的重要性 这一发现清楚地证明了正常皮肤功能的连接， 编码桥粒蛋白的几个基因的突变引起皮肤病。 此外，在某些自身免疫性疾病中，致病性自身抗体抑制 正常的桥粒功能，从而引起起泡性皮肤病。桥粒 在表皮的上层含有桥粒胶蛋白1（DSC 1）， 与桥粒芯糖蛋白1一起形成该连接的跨膜核心。DSC1 以两种亚型（dsc 1a，dsc 1b）表达，这两种亚型通过交替产生。 前体mRNA的剪接。近年来，在以下方面取得了进展： 了解dsc 1与其他桥粒的分子相互作用 proteins.然而，针对这些蛋白质的体内功能的研究 仍在进行中此外，根据其在桥粒中的作用， 形成和功能，我们假设dsc 1的突变可能导致 人类的皮肤病将讨论以下具体问题： dsc 1是形成功能性桥粒粘附复合物所必需的， 表皮，如果是这样，是否缺乏一个或两个剪接变体导致 与已知的“粘连病”或脆弱性相似的皮肤表型 综合征？两个dsc 1 splice的各自贡献是什么？ 桥粒功能的变体（a和B），即，细胞粘附和锚定 将中间丝细胞骨架连接到细胞膜上是 dsc 1的氨基末端结构域，像桥粒芯糖蛋白一样，对于其 在体内发挥作用？为了解决这些问题，我们将生成敲除/ 敲入缺乏一种或两种DSC 1剪接变体小鼠。 此外，我们将产生表达氨基端截短的 dsc 1，其在EC 1和EC 2结构域中具有氨基酸序列缺失。的 这里提出的动物模型不仅可以回答正常的 dsc 1在体内的功能，而且还可以模拟疾病表型， 识别可能由dsc 1功能受损引起的人类疾病。

DESCRIPTION: (verbatim) -- Desmosomes are cell adhesion structures (junctions) that are particularly abundant in the epidermis. The importance of these junctions for normal skin function was clearly demonstrated by the finding that mutations in several genes encoding desmosomal proteins cause skin diseases. Furthermore, in certain autoimmune diseases, pathogenic autoantibodies inhibit normal desmosome function, thereby causing blistering skin diseases. Desmosomes in the upper layers of the epidermis contain desmocollin 1 (dsc1) which, together with desmoglein 1, forms the transmembrane core of this junction. Dsc1 is expressed in two isoforms (dsc1a, dsc1b), that are generated by alternative splicing of the pre-mRNA. Progress has been made in recent years in understanding some of the molecular interactions of dsc1 with other desmosomal proteins. However, studies addressing the in vivo function of these proteins are still forthcoming. Furthermore, based on its proposed role in desmosome formation and function, we hypothesize that mutations in dsc1 might lead to skin disease in humans. The following specific questions will be addressed: Is dsc1 essential for the formation of a functional desmosomal adhesion complex in the epidermis and, if so, does the absence of one or both splice variants lead to a skin phenotype resembling known "adhesion diseases" or fragility syndromes? What are the individual contributions of the two dsc1 splice variants (a and b) to desmosome function, i.e., cell adhesion and anchoring of the intermediate filament cytoskeleton to the cell membrane? Is the amino-terminal domain of dsc1, like that of desmogleins, crucial for its function in vivo? To address these questions, we will generate knock out / knock in mice that are deficient for one or both dsc1 splice variants. Furthermore, we will generate mice that express an amino-terminally truncated dsc1 with a deletion of amino acid sequences in the EC1 and EC2 domains. The animal models proposed here will not only provide answers regarding the normal function of dsc1 in vivo, but also simulate disease phenotypes and help identify human diseases that might be caused by impaired dsc1 function.