Role of Cell Adhesion and the Cytoskeleton in Epidermal Integrity

 描述(申请人提供)：桥粒是细胞间的粘连结构，是表皮机械强度所必需的。在一些疾病中，桥粒的破坏会对皮肤的完整性造成破坏性的影响，包括寻常型天疱疮和某些类型的大疱性表皮松解症。桥粒蛋白的突变也会导致心肌病/发育不良。我们的长期目标是了解桥粒的组装和功能，以及细胞对其破坏的反应。桥粒的典型功能是在物理上连接细胞之间的角蛋白网络。虽然我们对介导角蛋白附着的直接物理相互作用有很好的了解，但还不知道桥粒是否会影响角蛋白的组装。我们已经确定了一种新的桥粒蛋白，它具有促进角蛋白细丝局部组装的独特能力。这改变了我们对桥粒的看法，从相对被动的结构，简单地将细胞骨架网络绑定到它们组装的主动调节器。我们将研究这种显著活性的机制和调节，这有望确定一条新的途径，以稳定桥粒和表皮完整性。我们的第二个目标将使用有针对性的蛋白质组学方法来识别新的和瞬时相关的桥粒蛋白。这将确定其他可能的疾病基因，并使未来能够定量确定不同疾病状态下桥粒组成的变化。最后，我们的第三个目标是解决细胞对桥粒丢失的反应。我们发现，桥粒破坏通过影响蛋白质的表达和定位，导致粘附素和紧密连接活性的显着变化。我们将确定细胞如何感知桥粒破坏，并确定控制其他细胞黏附结构变化的信号通路。总之，这些研究将增加或了解正常的桥粒功能和细胞对其扰动的反应，我们预计这将为桥粒相关疾病的诊断和治疗提供工具。

 DESCRIPTION (provided by applicant): Desmosomes are cell-cell adhesion structures that are required for the mechanical strength of the epidermis. Disruption of desmosomes results in devastating effects on skin integrity in diseases including pemphigus vulgaris/foliaceus and some types of epidermolysis bullosa. Mutations in desmosomal proteins also lead to cardiomyopathies/dysplasias. Our long-term goal is to understand the assembly and functions of desmosomes and the cellular responses to their disruption. The canonical function of desmosomes is to physically link keratin networks between cells. While we have a good understanding of the direct physical interactions that mediate keratin attachment, it is not known whether desmosomes affect keratin assembly. We have identified a novel desmosomal protein with the unique ability to promote the local assembly of keratin filaments. This changes our view of desmosomes from relatively passive structures that simply bind cytoskeletal networks to active modulators of their assembly. We will study the mechanism and regulation of this remarkable activity, which is expected to identify a novel pathway for desmosome stability and epidermal integrity. Our second aim will use a targeted proteomics approach to identify novel and transiently associated desmosomal proteins. This will identify additional putative disease genes and allow future quantitative determination of changes in desmosome composition in various disease states. Finally, our third aim addresses cellular responses to loss of desmosomes. We have found that desmosome disruption leads to dramatic changes in adherens and tight junction activity through effects on protein expression and localization. We will determine how cells sense desmosome disruption and determine the signaling pathways that control alterations of other cell adhesion structures. In total, these studies will increase or understanding of normal desmosome function and cellular responses to their perturbation which we expect to yield diagnostic and therapeutic tools for desmosome-related diseases.