Characterization of the Desmosome Protein Perp

桥粒蛋白 Perp 的表征

• 批准号: 7475278
• 负责人: LAURA D ATTARDI
• 金额: $ 33.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475278
• 关键词: Address; Adherens Junction; Adhesions; Adult; Affect; Affinity Chromatography; Aging; Antibodies; Biological Assay; Cell membrane; Cell-Cell Adhesion; Co-Immunoprecipitations; Condition; Cytoplasmic Tail; Defect; Desmosomes; Development; Disease; Ectoderm; Epidermis; Epithelial; Functional disorder; Future; Genetic; Growth Factor; Hair; Hair follicle structure; Homeostasis; Knock-out; Knockout Mice; Lead; Maintenance; Malignant Neoplasms; Membrane; Membrane Proteins; Molecular; Molecular Mechanisms of Action; Mouse Strains; Mus; Mutation; Nail plate; Nature; Neonatal; Numbers; Pathway interactions; Pemphigus Vulgaris; Phenotype; Physiological; Play; Post-Translational Protein Processing; Process; Program Development; Proteins; Regulation; Research Personnel; Role; Series; Skin; Stimulus; Structure; Sweat Glands; Tissues; Tooth structure; Transmembrane Domain; Wound Healing; appendage; base; defined contribution; extracellular; human disease; insight; loss of function; mutant; novel; programs; research study; trafficking; tumor progression

DESCRIPTION (provided by applicant): Human diseases associated with defects in cell-cell adhesion junctions known as desmosomes have suggested the importance of desmosomal components for the function and maintenance of the skin and ectodermal derivatives, including hair, teeth, nails, and sweat glands. Using knockout mice, we recently identified the Perp tetraspan membrane protein as a component of the p63 stratified epithelial development program, where it plays an essential role in desmosome function and epithelial adhesion in the skin. As a critical desmosomal constituent, Perp inactivation might lead to dysfunction of ectodermal derivatives. To address this hypothesis, we propose to use conditional mice we generated to ablate Perp specifically in the ectoderm and its derivatives and to determine the phenotypes arising in aging adult mice. Through this analysis, we will define the role of Perp in hair follicles, nails, teeth and sweat glands. As the role of desmosomes in ectoderm derivatives is not well understood, our studies will provide new insight into their role in these contexts. Moreover, revealing the consequences of Perp-deficiency in these tissue compartments provides a basis for identifying human diseases associated with Perp-deficiency in the future. To gain insight into the mechanism of Perp action at the desmosome, we will define important functional motifs within Perp by generating a panel of Perp mutants with alterations in specific domains and we will identify Perp-interacting desmosomal proteins. Finally, we propose to examine the role of Perp in the dynamic assembly and disassembly of desmosomes. To determine how Perp promotes desmosomal adhesion, we will establish whether Perp enhances trafficking, clustering or stability of desmosomal proteins at the plasma membrane. To define Perp's role in desmosome dissolution induced by a variety of physiological and pathological stimuli, including growth factors, wounding, and Pemphigus Vulgaris antibodies, we will examine Perp expression, localization and post-translational modification in these settings. These experiments will provide insight into a larger role that Perp may play in desmosome remodeling during such processes as development, wound healing, and cancer. Together, these approaches will provide an understanding of how Perp, desmosomes, and p63 contribute to both epithelial integrity and ectodermal appendage function, and how their dysfunction leads to disease.

描述（由申请人提供）：与细胞 - 细胞粘附连接中缺陷相关的人类疾病，称为脱染色体，已经表明了脱骨成分在皮肤和外胚层衍生物的功能和维护中的重要性，包括头发，牙齿，牙齿，指甲和汗腺。使用基因敲除小鼠，我们最近将Perp Tetraspan膜蛋白确定为p63分层上皮发育程序的组成部分，在该程序中，它在皮肤中的卵形组功能和上皮粘附中起着至关重要的作用。作为关键的脱发组成部分，perp灭活可能导致外胚层衍生物功能障碍。为了解决这一假设，我们提议使用我们在外胚层及其衍生物中生成的条件小鼠，并确定在衰老的成年小鼠中产生的表型。通过此分析，我们将定义PERP在毛囊，指甲，牙齿和汗腺中的作用。由于脱糖体在外胚层衍生物中的作用尚不清楚，因此我们的研究将为它们在这些情况下的作用提供新的见解。此外，揭示这些组织隔室中持久性缺陷的后果为识别未来与持久性缺陷相关的人类疾病提供了基础。为了深入了解脱骨体在脱发体上的机理，我们将通过生成在特定域中具有改变的PERP突变体来定义PERP内的重要功能基序，我们将识别出Perp相互作用的脱发蛋白。最后，我们建议检查PERP在脱糖体的动态组装和拆卸中的作用。为了确定PERP如何促进脱发粘附，我们将确定PERP是否可以增强质膜上脱乳小体蛋白的运输，聚类或稳定性。为了定义PERP在各种生理和病理刺激中引起的脱骨溶解中的作用，包括生长因子，伤害和垂体抗体抗体，我们将检查这些环境中的PERP表达，定位和翻译后修饰。这些实验将提供有关在发育，伤口愈合和癌症等过程中，PERP在脱骨体重塑中可能发挥的更大作用的洞察力。这些方法共同了解了perp，脱染色和p63如何有助于上皮完整性和外胚层附属功能，以及它们的功能障碍如何导致疾病。