| Co-Investigator(Kenkyū-buntansha) |
KIMURA Kiyonobu Iwamizawa Rosai Hospital, Department of INternal Medicine, Manager, 内科, 部長(研究職)
OHTSUKA Yoshinori Fukushima Medical University, Department of Medicine, Associate Professor, 医学部, 講師 (90301895)
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| Budget Amount *help |
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2003: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2002: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2001: ¥3,100,000 (Direct Cost: ¥3,100,000)
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| Research Abstract |
[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-
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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
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