Adhesion Junction Regulation in Normal and Diseased Skin

正常和患病皮肤的粘附连接调节

基本信息

批准号：
7430282
负责人：
DAVID S RUBENSTEIN
金额：
$ 35.81万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2012-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): We are interested in understanding (1) how cells regulate their ability to adhere to one another, (2) how cell-cell adhesion complexes might also function to transduce signals that inform the cell about the state of adhesion, a process known as signal transduction, and (3) the relationship of these regulatory events to human skin disease. This application represents the competitive continuation for this grant, which is funded through May 2006. Funding of this grant over the past 5 years has enabled us to (i) better understand the cell-cell adhesion and signaling functions of keratinocyte adherens junctions and desmosomes, (ii) begin to understand how these processes are regulated by phosphorylation and O-glycosylation, and (iii) begin to define the molecular mechanisms of acantholysis in the human autoimmune blistering disease pemphigus vulgaris (PV). Funding of this grant in the prior period has led to the following significant observations: (i) phosphorylation and O-glycosylation of mammalian beta-catenin and plakoglobin regulates the cell-cell adhesion and signaling function of these proteins, (ii) keratinocyte adherens junctions and desmosomes activate intracellular signaling systems, (iii) keratinocyte desmosomes are dynamic structures, and (iv) pemphigus autoantibodies activate desmosome-mediated signaling that appears to have a role in the mechanism of acantholysis in pemphigus. Therefore, funding of this grant in the prior period has led to the identification of and demonstration that inhibition of p38 MAPK represents a novel, rational, and practical therapeutic approach to treating pemphigus vulgaris. Additionally, stabilization of keratinocyte cell-cell adhesion by increased O-glycosylation may provide an additional therapeutic approach for treating blistering diseases. In this application we outline our plan to more deeply investigate the biology of keratinocyte cell-cell adhesion and desmosome signaling by (i) further defining the desmosome signaling pathway and mechanism of PV IgG acantholysis, (ii) determining the biological role played by HSP25/27 in PV acantholysis and cell-cell adhesion transitions, (iii) determining if PF IgG similarly activates desmosome signaling and identify similarities and differences between PV IgG (dsg3) and PF IgG (dsgl) mediated desmosome signaling. A significant outcome of these studies will be to translate these observations into effective treatments for pemphigus.

描述（由申请人提供）：我们有兴趣了解（1）细胞如何调节其相互粘附的能力，（2）细胞-细胞粘附复合物如何也可以发挥作用来转导信号，告知细胞粘附状态，一个称为信号转导的过程，以及（3）这些调节事件与人类皮肤病的关系。这项申请代表了这项拨款的竞争性延续，该拨款的资助截止到 2006 年 5 月。过去 5 年的这项拨款资助使我们能够 (i) 更好地了解角质形成细胞粘附连接和桥粒的细胞间粘附和信号传导功能， (ii) 开始了解这些过程如何通过磷酸化和 O-糖基化进行调节，以及 (iii) 开始定义人类自身免疫性水疱疾病中棘层松解症的分子机制寻常型天疱疮（PV）。前期的资助产生了以下重要观察结果：(i) 哺乳动物 β-连环蛋白和斑珠蛋白的磷酸化和 O-糖基化调节这些蛋白质的细胞间粘附和信号传导功能，(ii) 角质形成细胞粘附连接桥粒激活细胞内信号系统，(iii) 角质形成细胞桥粒是动态结构，(iv) 天疱疮自身抗体激活桥粒介导的信号，这似乎具有在天疱疮棘层松解机制中的作用。因此，前期的资助已经确定并证明了 p38 MAPK 的抑制代表了治疗寻常型天疱疮的一种新颖、合理且实用的治疗方法。此外，通过增加O-糖基化来稳定角质形成细胞的细胞间粘附可能为治疗水疱疾病提供另一种治疗方法。在本申请中，我们概述了我们的计划，通过（i）进一步定义PV IgG棘层松解的桥粒信号通路和机制，（ii）确定HSP25/所发挥的生物学作用，更深入地研究角质形成细胞细胞间粘附和桥粒信号传导的生物学。 27 在 PV 棘层松解和细胞间粘附转变中，(iii) 确定 PF IgG 是否类似地激活桥粒信号传导，并确定 PV IgG (dsg3) 和 PF IgG 之间的异同(dsgl) 介导的桥粒信号传导。这些研究的一个重要成果是将这些观察结果转化为天疱疮的有效治疗方法。