Investigation of molecular mechanism in the development of chronic obstructive pulmonary disease (COPD) using transgenic animal models.

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1.Analysis of the pulmonary emphysema in homozygous mutant klotho mouse (KL-/-).(1)Comparison of the gene-expression profile in the lung between KL-/-and wild-type mouse (WT).KL-/-, which lacks the klotho gene expression, develops emphysema at 4 weeks of age. We compared the gene-expression profile in the lung between KL-/-and WT at 2 weeks of age through hybridization method using Atlas Nylon Membranes. The genes including caspase 3, radical fringe homolog precursor related to a Notch signal transduction pathway, activin receptor IIA, IIB, and MAD homolog 7 related to TGF-beta family protein, were expressed more intensively in KL-/-lung than in WT lung. On the other hand, serine protease inhibitor 2 gene expressed less intensively in KL-/-lung. These findings suggest that deranged expression of the genes associated with lung development and apoptosis of pulmonary constituting cells participates in the pathogenesis of emphysema in klotho mice. The suppression of protease inhibitor activity, which protects lung from various injuries, is another contributing factor of it.(2)Investigation of therapy for emphysema In KL-/-.In male KL-/-, dietary phosphorus restriction upregulates the klotho gene expression. We investigated whether the upregulation of the klotho gene ameliorates emphysema in KL-/-. KL-/-at 3 weeks (younger group) and 5 weeks (elder group) were fed with phosphorus restricted (0.4%-P) diet for 2 and 4 weeks, respectively. The lungs of younger group did not develop emphysema while those of elder group showed severe emphysema. The replenishment of the klotho gene product is potentially useful in treating emphysema.2.Establishment of PCR system for sequencing the human klotho gene.The primer sets were designed for PCR in order to determine the DNA sequences of the human klotho gene.