Role of Cell Adhesion and the Cytoskeleton in Epidermal Integrity

 描述（由申请人提供）：桥粒是表皮机械强度所需的细胞-细胞粘附结构。在包括寻常型天疱疮/落叶型天疱疮和某些类型的大疱性表皮病的疾病中，桥粒的破坏对皮肤完整性产生破坏性影响。桥粒蛋白的突变也导致心肌病/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它们的破坏的反应。桥粒的典型功能是物理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理解，但尚不清楚桥粒是否影响角蛋白组装。我们已经确定了一种新的桥粒蛋白具有独特的能力，以促进角蛋白丝的局部组装。这改变了我们对桥粒的看法，从相对被动的结构，简单地结合细胞骨架网络，以主动调节其组装。我们将研究这种显著活性的机制和调控，这有望确定一种新的桥粒稳定性和表皮完整性的途径。我们的第二个目标将使用靶向蛋白质组学方法来识别新的和瞬时相关的桥粒蛋白。这将确定额外的推定的疾病基因，并允许未来定量测定桥粒组成的变化，在各种疾病状态。最后，我们的第三个目标是解决细胞对桥粒丢失的反应。我们已经发现，桥粒破坏通过影响蛋白质表达和定位导致粘附和紧密连接活性的显著变化。我们将确定细胞如何感知桥粒破坏，并确定控制其他细胞粘附结构改变的信号通路。总的来说，这些研究将增加或了解正常桥粒功能和细胞对它们的扰动的反应，我们期望产生桥粒相关疾病的诊断和治疗工具。

 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.