Lipid Raft Targeting of Desmoglein as a Mechanism for Desmosome Assembly

桥粒糖蛋白的脂筏靶向作为桥粒组装的机制

基本信息

批准号：
9051290
负责人：
Joshua David Lewis
金额：
$ 4.36万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-22 至 2018-02-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9051290
关键词：
Adhesives Adult Affect Architecture Binding Biology Bulla Cadherins Cell Adhesion Cell Proliferation Cell membrane Cell-Cell Adhesion Cells Cholesterol Clinical Cytokeratin filaments Data Defect Desmosomes Development Disease Dominant-Negative Mutation Down-Regulation Elements Endocytosis Epidermal Growth Factor Receptor Goals Heart Human Inherited Intercellular Junctions Intervention Kinetics Knowledge Life Maintenance Measures Mechanical Stress Mechanics Membrane Membrane Microdomains Modeling Mutate Mutation Organism Pathogenesis Patients Play Process Proteins Recruitment Activity Regulation Role Signal Transduction Skin Sphingolipids Syndrome Testing Tissues Transmembrane Domain Wound Healing blastocyst desmocollin desmoglein disease-causing mutation effective therapy human disease keratinocyte keratinocyte differentiation loss of function mutant novel therapeutic intervention prevent protein complex protein transport public health relevance skin disorder stem therapy design

项目摘要

DESCRIPTION (provided by applicant): Acquired and inherited skin blistering diseases are debilitating, life-altering illnesses. Many of these diseases are caused by a loss of desmosome function. Our ability to understand and design treatments for these diseases is hindered by our relatively poor understanding of basic desmosome biology. Very little is currently known about the regulation of desmosome assembly, or the means by which assembly becomes misregulated in various skin diseases. Data from our lab and others suggest desmosomes are assembled in microdomains of the plasma membrane known as lipid rafts. In order to understand the role that lipid rafts play in desmosome biology, we are examining the consequences of lipid raft association on the desmosomal cadherins known as desmogleins. We hypothesize that the desmoglein transmembrane domain targets this protein to lipid rafts, and that lipid raft association is necessary for incorporation into desmosomes and adhesive function. In our first aim, we will determine the role of lipid raft association in desmoglein function. In our second aim, we will determine how a mutation in the transmembrane domain of a desmoglein causes a human skin disease. Our long-term goal is to understand the mechanisms involved in regulating desmosomes and to identify new targets for potential intervention in pathogenesis. Resolving the mechanisms governing desmosome assembly would constitute an important advance in our understanding of cell-cell adhesion. This advance will also pave the way for new therapeutic strategies for treating an array of human skin diseases stemming from desmosomal misregulation.

描述（适用提供）：获得和遗传的皮肤起泡疾病正在使人衰弱，改变人生的疾病。这些疾病中的许多是由脱骨功能丧失引起的。我们对这些疾病的理解和设计治疗方法的能力受到了我们对基本脱发生物学的相对不良的理解。目前，关于脱骨组装的调节或组装在各种皮肤疾病中被误导的手段知之甚少。我们实验室和其他的数据表明，将脱糖体组装在称为脂质筏的质膜的微域中。为了理解脂筏在脱发生物学中的作用，我们正在研究脂质筏关联对脱粘蛋白的后果，称为脱木蛋白。我们假设Desmoglein跨膜结构域将该蛋白靶向脂质筏，而脂质筏的关联对于企业进入脱骨体和粘合功能是必不可少的。在我们的第一个目标中，我们将确定脂质筏关联在去蛋白酶功能中的作用。在我们的第二个目标中，我们将确定desmoglein跨膜结构域中的突变如何引起人皮肤病。我们的长期目标是了解调节脱糖体中涉及的机制，并确定潜在的发病机理干预目标。解决有关脱骨组装的机制将构成我们对细胞细胞粘附的理解的重要进步。这项进步还将为新的治疗策略铺平道路，以治疗因脱骨膜不调节而导致的一系列人体皮肤疾病。