Genetic Defect of Fibrillin and Scleroderma

原纤维蛋白和硬皮病的遗传缺陷

• 批准号: 6345913
• 负责人: CONSTANTIN A BONA
• 金额: $ 16.67万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6345913
• 关键词: T lymphocyte; autoantibody; cellular pathology; elastin; extracellular matrix proteins; fibrillin; fibroblasts; gene mutation; genetically modified animals; laboratory mouse; model design /development; molecular pathology; protein biosynthesis; scleroderma; tissue /cell culture; transfection

Tight skin (TSK) is an autosomal dominant mutation in mice characterized by excessive accumulation of type I and III collagens and glycosaminoglycans in the skin and various internal organs. The TSK mouse represents an animal model for human scleroderma because it has similar involvement of the skin and is associated with autoimmune phenomena. Recently, the TSK syndrome has been linked to a partial duplication of fibrillin-1 gene predicted to encode a 418kD polypeptide containing 948 amino acids in addition to 312kD normal protein. However, there is no formal demonstration that TSK mutation is similar to fibrillin-1 (Fbn-1) mutation. Fibrillins are constitutes of microfibrils. The production of microfibrils is increased and their structure is altered in scleroderma and TSK mouse. Ongoing studies carried out in the laboratory showed a high incidence of anti Fbn-1 autoantibodies in TSK/+ mice and in Choctaw Indian tribe compared to normal mice or healthy Choctaw individuals. The specific aims of the proposal are: 1. To study whether Tg mice expressing duplicated Fbn-1 gene exhibit the TSK syndrome and whether the fibroblasts express a stable fibrogenic phenotype and to determine whether injection of naked DNA expressing mutated Fbn-1 gene causes local sclerosis. 2. The preparation of characterization of Fbn-1 or elastin specific T cell clones and to study their effects on the production of extracellular matrix proteins by fibroblasts. 3. To study the presence of anti-Fbn-1 autoantibodies in Ssc and other kindred connective tissue diseases.

皮肤紧绷（TSK）是小鼠的一种常染色体显性突变，其特征是皮肤和各种内脏器官中I型和III型胶原和糖胺聚糖的过度积累。 TSK小鼠代表人类硬皮病的动物模型，因为它具有类似的皮肤受累并且与自身免疫现象相关。 最近，TSK综合征已被链接到一个部分重复的repeatin-1基因预测，编码一个418 kD的多肽含有948个氨基酸除了312 kD正常蛋白质。 然而，没有正式的证据表明TSK突变与Fbn-1突变相似。 原纤维蛋白由微纤维组成。在硬皮病和TSK小鼠中，微纤维的产生增加并且它们的结构改变。 正在进行的实验室研究显示，与正常小鼠或健康乔托个体相比，TSK/+小鼠和乔托印第安部落中抗Fbn-1自身抗体的发生率较高。 该提案的具体目标是：1。研究表达重复Fbn-1基因的Tg小鼠是否表现出TSK综合征，成纤维细胞是否表达稳定的纤维化表型，并确定注射表达突变Fbn-1基因的裸DNA是否引起局部硬化。 2.制备Fbn-1或弹性蛋白特异性T细胞克隆的表征，并研究它们对成纤维细胞产生细胞外基质蛋白的影响。 3.目的：研究抗Fbn-1自身抗体在Ssc及其它结缔组织病中的存在情况。