FUNCTION OF PEMPHIGUS VULGARIS ANTIGEN

寻常型天疱疮抗原的功能

• 批准号: 6171528
• 负责人: John R Stanley
• 金额: $ 25.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171528
• 关键词: autoantibody; autoantigens; cell adhesion; cellular pathology; clinical research; disease /disorder model; gene targeting; human subject; human tissue; immunologic assay /test; laboratory mouse; laboratory rabbit; model design /development; pemphigus; protein structure function; tissue /cell culture; transfection

DESCRIPTION: (Adapted from the applicant's abstract) Pemphigus vulgaris (PV) is a life-threatening blistering skin disease in which autoantibodies against the cell surface of keratinocytes cause them to separate. Autoantibodies from these patients identify PVA or Dsg3 which is a desmosomal molecule in the desmoglein subfamily of the cadherin supergene family. The original cadherins have been shown to be calcium-dependent cell adhesion molecules. The hypothesis of this proposal is that PVA, like classical cadherins, functions in adhesion and that autoantibodies cause loss of function. Therefore, the general goal of this proposal is to determine the function of PVA and how PV autoantibodies cause disease. The first specific aim is to determine if the extracellular (EC) domain of PVA can mediate homophilic adhesion by examining aggregation of transfected fibroblasts or by producing the EC domain with baculovirus and examining directly its function outside of cells. The second specific aim is to study the functions of the intracellular (IC) subdomains of PVA to determine which regions: bind plakoglobin, confer adhesive function on the EC domain, and direct PVA to the desmosome. The third specific aim is to examine function of PVA in normal tissues by establishing mice genetically deficient in PVA by targeted disruption of the gene with homologous recombination. Examining these mice for phenotypic abnormalities is an in vivo approach for studying possible roles of PVA in normal tissue development, structure, and function. Finally, specific aim four is to establish animal models of PV to determine which subdomains of PVA are involved in disease activity. The studies addressing this aim will also result in valuable anti-Dsg3 reagents. Overall, the applicants expect that this proposal will advance our knowledge not only of tissue specific autoimmune disease but also of the normal mechanisms of epithelial cell adhesion.

描述：(改编自申请者摘要)寻常型天疱疮 (PV)是一种危及生命的水疱性皮肤病，其自身抗体 在角质形成细胞的细胞表面上，导致它们分离。 这些患者的自身抗体识别PVA或Dsg3，这是一种 钙粘附素上基因桥粒蛋白亚家族中的桥粒分子 一家人。最初的钙粘附素已被证明是钙依赖细胞。 黏附分子。这一提议的假设是PVA，就像 经典钙粘附素在粘连中的作用以及自身抗体引起的 功能丧失。因此，这项建议的总目标是 确定PVA的功能以及PV自身抗体如何导致疾病。这个 第一个特定目标是确定PVA的胞外(EC)结构域 通过检测转基因细胞的聚集性来介导同种异体黏附 成纤维细胞或通过杆状病毒产生EC结构域并检测 直接在细胞外发挥作用。第二个具体目标是研究 PVA细胞内(IC)亚域的功能决定哪些 区域：结合蛋白，赋予EC结构域的黏附功能，以及 将PVA定向到桥粒。第三个具体目标是检查功能 通过建立PVA基因缺陷小鼠来检测正常组织中的PVA 通过同源重组靶向破坏基因。检视 这些小鼠的表型异常是一种活体研究的方法 PVA在正常组织发育、结构和功能中的可能作用。 最后，具体目的四是建立PV动物模型，以确定 PVA的哪些亚域参与疾病活动。这些研究 解决这一目标也将产生有价值的抗Dsg3试剂。 总体而言，申请者希望这项建议将增进我们的知识 不仅是组织特异性自身免疫性疾病，而且是正常的 上皮细胞黏附的机制。