Translational Regulation by Desmosomes

桥粒的翻译调节

• 批准号: 10314319
• 负责人: Terry H Lechler
• 金额: $ 38.96万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314319
• 关键词: Acute; Adhesions; Antibodies; Autoimmune Diseases; Binding; Biogenesis; Biology; Bulla; Cardiomyopathies; Cell Adhesion; Cell-Cell Adhesion; Cells; Complex; Cytoskeleton; Data; Defect; Desmosomes; Dysplasia; Elements; Epidermis; Epithelial; Gene Expression; Genes; Genetic Diseases; Genetic Transcription; Genetic Translation; Goals; Heart; Image; Immunofluorescence Immunologic; Intermediate Filaments; Location; Mechanics; Mediating; Messenger RNA; MicroRNAs; Pathogenicity; Pathway interactions; Pattern; Pemphigus; Phosphorylation; Physiology; Polyribosomes; Protein Family; Proteins; Proteomics; RNA-Induced Silencing Complex; Ribosomal Proteins; Ribosomes; Role; Signal Transduction; Site; Skin; Structure; Tissues; Transcript; Translational Regulation; Translations; Work; base; cell cortex; imaging approach; novel; phosphoproteomics; recruit; resilience; response; sensor; single molecule; skin disorder; spatiotemporal; translatome; wound healing

Abstract Desmosomes are cell-cell adhesion structures that are essential for the mechanical strength of the epidermis and heart. Disruption of desmosomes results in devastating blistering diseases of the skin and in cardiomyopathies/dysplasias. While the canonical role of desmosomes is to provide mechanical resilience through binding the intermediate filament cytoskeleton, emerging non- canonical functions suggest that desmosomes are important integrators of many aspects of tissue physiology. Our long-term goals are to understand the functions of desmosomes in the epidermis and to determine how cells respond to pathogenic anti-desmosomal antibodies produced in the autoimmune diseases, pemphigus. We have made the exciting discovery that desmosomes recruit translational regulators to the cell cortex. We hypothesize that desmosomes are sensors of tissue integrity that alter translation in response to defective adhesion. To define the functional relevance of translational control by desmosomes, we will determine the translational response upon acute disruption of desmosomes using pathogenic pemphigus antibodies. In addition, we will use single molecule live-imaging approaches to determine the sites of protein translation under both homeostatic conditions and when desmosomes are disrupted. This work will define novel mechanisms for cell adhesions in regulating post-transcriptional gene expression, which may have essential functions in sensing and responding to defects in epithelial integrity.

摘要 桥粒是细胞-细胞间的黏附结构，对关节盘的机械强度至关重要。 表皮和心脏。桥粒的破坏会导致毁灭性的水泡性疾病 皮肤和心肌病/发育不良。而桥粒的典型作用是提供 机械韧性通过结合中间丝细胞骨架，出现非 典型功能提示桥粒是组织许多方面的重要整合因子 生理学。我们的长期目标是了解表皮中桥粒的功能。 并确定细胞对致病性抗桥粒抗体的反应 自身免疫性疾病，天疱疮。我们有了一个令人兴奋的发现，桥粒招募 翻译调节因子到细胞皮质。我们假设桥粒是组织的传感器 由于粘合缺陷而改变翻译的完整性。定义功能关联性 桥粒的翻译控制，我们将确定翻译反应在急性 使用致病性天疱疮抗体破坏桥粒。此外，我们还将使用Single 用分子活体成像方法确定蛋白质在两者作用下的翻译位点 动态平衡状态和桥粒被破坏的时间。这部作品将给小说下定义 细胞黏附调节转录后基因表达的机制，这可能有 在感知和响应上皮完整性缺陷方面的基本功能。