Investigation of Pulmonary Fibrosis Susceptibility Gene : from Silicosis Mouse to IIP and SIlicosis Patients

肺纤维化易感基因的调查：从矽肺小鼠到IIP和矽肺患者

• 批准号: 13470129
• 负责人: MUNAKATA Mitsuru
• 金额: $ 8.32万
• 依托单位: Fukushima Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470129/
• 关键词: silica; silicosis; susceptibility gene; TNF-alpha; MBL; PMF; Inbred Mouse; 遺伝子多型; ヒト

[Mouse Model] We have performed genome-wide linkage analysis to elucidate the susceptibility genes to pulmonary fibrosis in mice. From our previous study, we have found genetic contribution to pulmonary response to silica exposure, and that C57BL/6J (B6) was the most susceptible strain and CBA/J (CBA) was the resistant one among 8 strains of mice. In order to identify responsible genes in response to silicosis, we bred intercross (F2) between B6 and CBA. Agenome-wide linkage analysis of quantitative trait loci (QTLs) was performed using Map Manager QTX. As an index of fibrosis, hydroxyproline was applied, and genotypes of 167 marker genes were analyzed. A genome-wide linkage analysis of silica exposed F2 cohort identified significant QTL on chromosome 4 and suggestive QTLs on chromosomes 3 and 18 respectively.[Silicosis Patients] To explain individual variability in response to silica exposure, we have made our hypothesis that there might be an association between polymorphisms of TNF- … More alpha or mannose binding lectin (MBL) and lung response to silica particle. To examine this, we have studied the association of TNF-alpha promoter polymorphisms (-308, -238, -376) with nodular silicosis (n=84), and progressive massive fibrosis (PMF) (n=44), and healthy controls (n=122). Results showed that frequency of -308A allele frequency was significantly higher in silicosis compared to controls (6.35% and 2.05%, p<0.01). It was also significantly higher in patients with nodular silicosis compared to PMF (p<0.05). These results suggest that TNF-alpha-308A might enhance susceptibility to nodular silicosis. We also have studied the, association of MBL codon 54, which is common in Japanese population, with nodular lesion (n=97), PMF (n=48), and healthy controls (n=84). PMF group had significantly higher frequency of mutant allele than control group (19.80%, 12.9% respectively, p<0.05). These results suggest that MBL codon 54 mutant allele might enhance the development of PMF in silicosis. Less

【小鼠模型】我们进行了全基因组连锁分析来阐明小鼠肺纤维化的易感基因。通过前期研究，我们发现肺对二氧化硅暴露的反应与遗传有关，8株小鼠中C57BL/6J （B6）最敏感，CBA/J （CBA）最耐药。为了确定对矽肺反应负责的基因，我们在B6和CBA之间进行了杂交（F2）。使用Map Manager QTX进行全基因组数量性状位点（QTLs）连锁分析。采用羟脯氨酸作为纤维化指标，分析167个标记基因的基因型。对暴露于二氧化硅的F2群体进行全基因组连锁分析，发现4号染色体上有显著性QTL， 3号染色体和18号染色体上分别有提示性QTL。[矽肺病患者]为了解释个体对二氧化硅暴露的反应差异，我们提出了我们的假设，即TNF-…More α或甘露糖结合凝集素（MBL）多态性与肺部对二氧化硅颗粒的反应之间可能存在关联。为了检验这一点，我们研究了tnf - α启动子多态性（-308,-238,-376）与结节性矽肺病（n=84）、进行性大规模纤维化（n=44）和健康对照（n=122）的关系。结果显示，矽肺患者-308A等位基因频率显著高于对照组（6.35%和2.05%,p<0.01）。结节性矽肺患者与PMF患者相比也显著增高（p<0.05）。这些结果提示tnf - 308a可能增加结节性矽肺的易感性。我们还研究了日本人群中常见的MBL密码子54与结节性病变（n=97）、PMF （n=48）和健康对照（n=84）的关系。PMF组突变等位基因频率显著高于对照组（分别为19.80%、12.9%,p<0.05）。这些结果提示MBL密码子54突变等位基因可能促进矽肺PMF的发展。少

项目成果

T.Takahashi, M.Munakta, Y.Ohtsuka, et al.: "Expression and alteration of Ras and p53 proteins in patients with lung carcinoma accompanied by idiopathic pulmonary fibrosis."Cancer. 95. 624-633 (2002)

T.Takahashi、M.Munakta、Y.Ohtsuka 等人：“伴有特发性肺纤维化的肺癌患者中 Ras 和 p53 蛋白的表达和改变。”癌症。

K.Uekita, Y.Ohtsuka, M.Munakata, et al.: "A case of Hermansky Pudlal syndrome"Int Med. (In press). (2004)

K.Uekita、Y.Ohtsuka、M.Munakata 等人：“赫曼斯基普德拉尔综合征一例”Int Med。

大塚義紀, 棟方 充: "閉塞性肺疾患と気道系疾患.気管支喘息「呼吸器疾患の治療と看護」(工藤翔二 編)"南江堂. 213-218 (2002)

Yoshiki Otsuka、Mitsuru Munakata：“阻塞性肺疾病和呼吸道疾病。支气管哮喘‘呼吸系统疾病的治疗和护理’（工藤正司编辑）”Nankodo 213-218（2002）。

Y.Ohtsuka, X.Wang, K.Kimura, M.Munakata: "Mannose Binding Lectin (MBL) gene polymorphism and the development of progressive massive fibrosis."Am J Respir Crit Care Med. 167. A258 (2003)

Y.Ohtsuka、X.Wang、K.Kimura、M.Munakata：“甘露糖结合凝集素 (MBL) 基因多态性与进行性大规模纤维化的发展。”Am J Respir Crit Care Med。

Y.Ohtsuka, X.Wang, K.Kimura, M.Munakata, et al.: "Polymorphismas in the promoter of TNF alpha gene in patients with silicosis and progressive massive fibrosis."Thorax. 57. ii40 (2003)

Y.Ohtsuka、X.Wang、K.Kimura、M.Munakata 等人：“矽肺和进行性大块纤维化患者 TNF α 基因启动子的多态性。”胸部。