Genetic Defect of Fibrillin and Scleroderma

紧致皮肤（TSK）是小鼠的常染色体显性突变，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小鼠代表了人类硬皮病的动物模型，因为它有类似的皮肤受累，并与自身免疫现象有关。最近，TSK综合征与纤颤蛋白1基因的部分重复有关，该基因编码一个418kD的多肽，除了312kD的正常蛋白外，还含有948个氨基酸。然而，没有正式的证据表明TSK突变与纤原蛋白-1 （Fbn-1）突变相似。纤原蛋白由微原纤维组成。在硬皮病和TSK小鼠中，微原纤维的产生增加，其结构发生改变。正在实验室进行的研究表明，与正常小鼠或健康的乔克托族个体相比，TSK/+小鼠和乔克托族印第安部落中抗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小鼠是否表现为TSK综合征，成纤维细胞是否表达稳定的成纤维表型，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. Fbn-1或弹性蛋白特异性T细胞克隆的制备及其对成纤维细胞生成细胞外基质蛋白的影响。3. 目的：研究抗fbn -1自身抗体在Ssc及其他同类结缔组织疾病中的存在。

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.