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Regulation of desmosomal hyperadhesion in epidermal barrier function and tissue integrity

桥粒过度粘附对表皮屏障功能和组织完整性的调节

基本信息

批准号：
326600997
负责人：
Professorin Dr. Mechthild Hatzfeld
金额：
--
依托单位：
Arbeitsgruppe Pathobiochemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/326600997?language=en
关键词：
Regulation desmosomal hyperadhesion epidermal barrier

项目摘要

Desmosomes are cell-cell adhesive structures essential for tissue integrity of the epidermis. Their constituents belong to multigene families giving rise to desmosomes of variable composition. So far, the functional significance of context-dependent composition in desmosome formation, dynamics or stability during epidermal differentiation is incompletely understood. Desmosomes can occur in two functionally distinct adhesive states, which are distinguished by their reaction to calcium depletion: In normal tissues, desmosomes adopt a calcium-independent state, also referred to as hyperadhesion. In contrast, during regeneration and wound healing, desmosomal adhesion becomes calcium-dependent resulting in weaker intercellular cohesion that allows for tissue remodeling. So far little is known about the differential contribution of individual desmosomal proteins to hyperadhesion. We have recently shown that plakophilins 1 and 3, components of the desmosomal plaque with distinct expression patterns in the epidermis, differ fundamentally in their contribution to stable intercellular adhesion: Whereas plakophilin 1 was required for hyperadhesion and thus stability plakophilin 3 conferred a dynamic state compatible with plasticity. Moreover, we have demonstrated that the localization and function of plakophilin 1 in the desmosome is regulated by its phosphorylation via IGF-1/insulin signaling.The aim of the current proposal is to elucidate the mechanisms leading to hyperadhesion and at the same time allowing reversion thus facilitating remodeling and plasticity of desmosomes. To this extent we will analyze how desmosome composition contributes to a hyperadhesive versus a dynamic state and which molecular mechanisms regulate these states and their interconversion. Although findings suggest a role of PKCalpha in this process neither its targets in the desmosome nor the precise mechanism how PKCalpha modulates desmosomal protein interactions or localization have been studied. Moreover, desmosomal proteins including the desmosomal cadherins and plakophilins become palmitoylated. Again, neither the function of this modification in desmosomal dynamics and stability nor the relevant enzymes have been studied. Finally, we will characterize the physiological role of hyperadhesive versus dynamic desmosomes in epidermal barrier function and tissue integrity.We expect that our studies provide novel insight into the regulation of desmosome dependent adhesion and barrier function during epidermal differentiation and regeneration. Moreover, the identification of those desmosomal proteins that are essential for hyperadhesion and their regulation will enable us to address the question if and how hyperadhesion can protect from tissue damage by mechanical and other stresses leading to atopic dermatitis, psoriasis or the autoimmune disease Pemphigus vulgaris.

桥粒是一种细胞-细胞黏附结构，对表皮的组织完整性至关重要。它们的组成属于多基因家族，产生组成不同的桥粒。到目前为止，上下文相关成分在桥粒形成、表皮分化过程中的动力学或稳定性中的功能意义还不完全清楚。桥粒可以在两种功能不同的粘连状态下出现，这两种状态的区别是对钙耗竭的反应：在正常组织中，桥粒采用钙非依赖性状态，也称为过度粘连。相反，在再生和伤口愈合期间，桥粒粘连变得依赖于钙，导致细胞间粘附力较弱，从而允许组织重塑。到目前为止，关于单个桥粒蛋白在高黏附中的不同作用还知之甚少。我们最近发现，亲斑蛋白1和3是桥粒斑块的组成部分，在表皮中有不同的表达模式，它们对稳定的细胞间黏附的贡献是根本不同的：而亲斑黏附蛋白1是高黏附所必需的，因此稳定的黏附黏附蛋白3赋予了与可塑性相容的动态状态。此外，我们还证明了平台亲和素1在桥粒中的定位和功能受其通过IGF-1/胰岛素信号的磷酸化调节。本研究的目的是阐明导致桥粒高度黏附的机制，同时允许逆转，从而促进桥粒的重塑和可塑性。在这一点上，我们将分析桥粒组成如何促进超粘附性而不是动态，以及哪些分子机制调节这些状态及其相互转化。虽然研究结果表明PKCalpha在这一过程中发挥了作用，但它的靶标在桥粒中，也没有研究PKCalpha如何调控桥粒蛋白相互作用或定位的确切机制。此外，桥粒蛋白，包括桥粒钙粘附素和嗜血小板蛋白，会发生棕榈酰化。同样，这种修饰在桥粒动力学和稳定性中的作用以及相关的酶都没有研究过。最后，我们将对高粘附性桥粒和动态桥粒在表皮屏障功能和组织完整性中的生理作用进行表征。我们的研究有望为研究桥粒依赖的黏附和屏障功能在表皮分化和再生过程中的调控提供新的视角。此外，识别那些对高黏附至关重要的桥粒蛋白及其调控将使我们能够解决高黏附是否以及如何保护组织免受机械和其他应激导致的特应性皮炎、牛皮癣或自身免疫性疾病寻常型天疱疮的损害。