Role of Cell Adhesion and the Cytoskeleton in Epidermal Integrity

细胞粘附和细胞骨架在表皮完整性中的作用

• 批准号: 8961762
• 负责人: Terry H Lechler
• 金额: $ 33.97万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8961762
• 关键词: Address; Adherens Junction; Adhesions; Affect; Antibodies; Autoantibodies; Autoimmune Diseases; Bacterial Infections; Binding; Biochemistry; Biology; Biotinylation; Bulla; Cadherins; Candidate Disease Gene; Cardiomyopathies; Cell Adhesion; Cell Line; Cell physiology; Cell-Cell Adhesion; Cells; Cellular biology; Complement; Cytokeratin filaments; Cytoskeleton; Data; Defect; Desmosomes; Diagnostic; Disease; Dysplasia; Epidermis; Epidermolysis Bullosa; Filament; Future; Genes; Genetic; Goals; Hereditary Disease; In Vitro; Keratin; Knowledge; Lead; Learning; Link; Mass Spectrum Analysis; Mechanics; Mediating; Microtubules; Mus; Mutation; Myosin Type II; Null Lymphocytes; Pathogenesis; Pathology; Pathway interactions; Patients; Pemphigus; Pemphigus Vulgaris; Physiology; Proteins; Proteomics; Regulation; Role; Signal Pathway; Signal Transduction; Skin; Staging; Structure; Testing; Therapeutic; Tight Junctions; Tissues; Transgenic Organisms; Vinculin; Work; Wound Healing; assault; base; beta catenin; cell motility; claudin-1 protein; epidermis cell; in vivo; keratinocyte; loss of function mutation; new therapeutic target; novel; novel diagnostics; protein expression; public health relevance; response; therapeutic target; tool

 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.

 描述（由申请人提供）：桥粒是表皮机械强度所需的细胞间粘附结构。桥粒的破坏会对寻常型天疱疮/落叶型天疱疮和某些类型的大疱性表皮松解症等疾病的皮肤完整性造成破坏性影响。桥粒蛋白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细胞之间物理连接角蛋白网络。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，但尚不清楚桥粒是否影响角蛋白组装。我们发现了一种新型桥粒蛋白，具有促进角蛋白丝局部组装的独特能力。这改变了我们对桥粒的看法，从简单地将细胞骨架网络与其组装的主动调节剂结合的相对被动结构。我们将研究这种显着活性的机制和调节，有望找到桥粒稳定性和表皮完整性的新途径。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型且短暂相关的桥粒蛋白。这将鉴定额外的假定疾病基因，并允许未来定量确定各种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表达和定位，导致粘附和紧密连接活性发生巨大变化。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其扰动的反应，我们期望为桥粒相关疾病提供诊断和治疗工具。