FAMILIAL PULMONARY FIBROSIS

家族性肺纤维化（FPF）是一种遗传性肺纤维化疾病， 病因不明，临床和病理学与 特发性肺纤维化，除了它发生在家庭。 模式 与常染色体显性基因的遗传相容， 变折射率 本提案的总体目标是研究 家族性肺纤维化的分子遗传学 具体目标是 （1）招募并临床表征肺纤维化家族 和（2）进行限制性片段长度多态性（RFLP）分析， 这些家庭的成员，随后进行连锁分析的候选基因。 FPF可能是由于基因或组的异常， 控制免疫或炎症过程的基因。 可选择地， 编码间质胶原蛋白的基因的遗传异常 可能参与其中。 我们认为编码I型和III型的基因 前胶原或HLA基因座是FPF基因座的候选基因。这 将通过对具有以下特征的个体进行RFLP分析来检验假设： FPF之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性 I型前胶原蛋白 更多的家庭将被招募和评估 临床上用于治疗间质性肺病。 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族 (BAL)液体检测无症状的肺泡炎患者谁可能在一个 疾病的临床前阶段或可能表现为不完全性痴呆的患者 FPF基因。 将评价BAL液的炎症变化， “激活”肺泡巨噬细胞。 RFLP分析将 通过用限制性内切酶消化DNA和Southern杂交进行 使用放射性标记的探针对消化的DNA片段进行印迹分析， 胶原蛋白的前α 2（I）、前α 1（I）或前α 1（III）链 以及HLA标记的探针。 将进行连锁分析 以确定FPF是否与基因编码异常有关， I型和III型前胶原和HLA基因座。 如果显示链接 在临床综合征和特定基因型之间，这将提供 有力的证据表明，这种疾病是由于异常的胶原蛋白 基因或免疫系统。 如果成立，这一发现将 纤维化肺疾病的发病机制的重要影响。 它也可能在确定遗传易感性方面具有重要意义。 环境纤维化肺病

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.