Lipid Raft Targeting of Desmoglein as a Mechanism for Desmosome Assembly

 描述（由申请人提供）：获得性和遗传性皮肤起泡疾病是使人衰弱，改变生活的疾病。这些疾病中的许多是由桥粒功能的丧失引起的。我们理解和设计这些疾病的治疗方法的能力受到我们对基本桥粒生物学相对较差的理解的阻碍。目前对桥粒组装的调节或组装在各种皮肤病中失调的方式知之甚少。来自我们实验室和其他实验室的数据表明，桥粒组装在质膜的微区中，称为脂筏。为了了解脂筏在桥粒生物学中的作用，我们正在研究脂筏结合对桥粒钙粘蛋白（称为桥粒糖蛋白）的影响。我们假设桥粒芯糖蛋白跨膜结构域的目标，这种蛋白质的脂筏，脂筏协会是必要的纳入桥粒和粘附功能。在我们的第一个目标，我们将确定的作用，脂筏协会桥粒芯蛋白功能。在我们的第二个目标中，我们将确定桥粒芯糖蛋白跨膜结构域的突变如何导致人类皮肤病。我们的长期目标是了解参与调节桥粒的机制，并确定潜在干预发病机制的新靶点。解决桥粒组装的机制将构成我们对细胞-细胞粘附理解的重要进展。这一进展也将为治疗一系列源于桥粒失调的人类皮肤病的新治疗策略铺平道路。

 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.