FAMILIAL PULMONARY FIBROSIS

家族性肺纤维化是一种遗传性肺纤维化。 临床和病理上相同的未知病因 特发性肺纤维化，除非它发生在家族中。该模式 遗传与常染色体显性基因的遗传是相容的 可变的外显度。这项建议的总体目标是研究 家族性肺纤维化的分子遗传学研究。具体目标是 (1)招募肺纤维化家系并对其临床特征进行分析 进行限制性片段长度多态性(RFLP)分析 对这些家族成员进行候选基因的连锁分析。 可能是由于FFP的基因或组的异常 控制免疫或炎症过程的基因。或者， 间质胶原基因编码的一种遗传异常 可能牵涉其中。我们认为编码I型和III型的基因 前胶原基因或人类白细胞抗原基因座是FPF基因座的候选基因。这 假说将通过对患有以下疾病的个人进行RFLP分析来检验 然后对这些候选基因进行连锁分析。初步 三个家系的数据显示两个限制性内切酶位点的多态 对于I型前胶原。将招募和评估更多的家庭 临床上为间质性肺病的存在。的所有成员 将通过分析支气管肺泡灌洗来研究信息丰富的家庭 (BAL)液体以检测无症状的肺泡炎患者可能处于 疾病的临床前阶段或可能代表不完全外露的人 Fpf基因。将评估BAL液体的炎性变化和 “激活”的肺泡巨噬细胞。RFLP分析将是 用限制性内切酶和Southern对DNA进行消化 用放射性标记探针对消化的DNA片段进行印迹分析 胶原蛋白的前α2(I)、前α1(I)或前α1(III)链 以及人类白细胞抗原标记物的探针。将执行连锁分析 以确定FPF是否与基因编码异常有关 对于I型和III型前胶原和一个人类白细胞抗原基因座。如果显示链接 在临床综合征和特定的基因型别之间，这将提供 强有力的证据表明这种疾病是由于胶原蛋白的异常引起的 基因或免疫系统。如果得到证实，这一发现将会 对纤维性肺疾病发病机制的重要意义。 它也可能在确定遗传易感性方面具有重要意义。 环境纤维性肺病。

Familial pulmonary fibrosis (FPF) is an inherited fibrotic lung disorder of unknown etiology which is clinically and pathologically identical to idiopathic pulmonary fibrosis except that it occurs in families. The mode of inheritance is compatible with that of an autosomal dominant gene with variable penetrance. The overall goal of this proposal is to study the molecular genetics of familial pulmonary fibrosis. The specific aims are to (1) recruit and clinically characterize families with pulmonary fibrosis and (2) perform restriction fragment length polymorphism (RFLP) analysis on members of these families followed by linkage analysis to candidate genes. It is possible that FPF is due to an abnormality in the gene or group of genes which control immunologic or inflammatory processes. Alternatively, a genetic abnormality in the genes coding for the interstitial collagens may be involved. We propose that genes coding for types I and III procollagen or an HLA locus are candidate genes for the FPF locus. This hypothesis will be tested by performing RFLP analysis on individuals with FPF followed by linkage analysis for these candidate genes. Preliminary data in three families show polymorphism for two restriction enzyme sites for type I procollagen. More families will be recruited and evaluated clinically for the presence of interstitial lung disease. All members of informative families will be studied by analysis of bronchoalveolar lavage (BAL) fluid to detect asymptomatic patients with alveolitis who may be in a preclinical phase of the disease or who may represent incomplete penetrance of the FPF gene. BAL fluid will be evaluated for inflammatory changes and "activated" pulmonary alveolar macrophages. RFLP analysis will be performed by digestion of DNA with restriction endonucleases and Southern blot analysis of the digested DNA fragments using radiolabelled probes for the pro-alpha 2(I), pro-alpha 1(I) or pro-alpha 1(III) chains of collagen as well as a probe for an HLA marker. Linkage analysis will be performed to determine whether FPF is associated with an abnormality in genes coding for types I and III procollagens and an HLA locus. If linkage is shown between the clinical syndrome and a specific genotype, this would provide strong evidence that the disease is due to an abnormality in the collagen genes or the immune system. If established, this finding would have important implications for the pathogenesis of fibrosing lung disorders. It might also have importance in establishing genetic susceptibility to environmental fibrosing lung diseases.