|Budget Amount *help
¥2,900,000 (Direct Cost : ¥2,900,000)
Fiscal Year 2003 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 2002 : ¥2,000,000 (Direct Cost : ¥2,000,000)
1. Verification of efficacy of intraperitoneal injection of peptide LSKL on an animal model of liver damage: To confirm the inhibitory mechanism for TGF-β activation by the peptide on the DMN-treated rat model of liver damage and fibrosis, we estimated the phosphorylation level of Smad 2 which demonstrates the signal transduction of TGF-β-receptor activation. Installing the data, we published a paper entitled "A blocking peptide for transforming growth factor-β1 activation prevents hepatic fibrosis in vivo" (J Hepatol 39, 2003).
2. Evaluation of the efficacy of enteral application of peptide LSKL : LSKL and SLLK (mock peptide) were applied perorally at a dose of 1mg/1OOg BW/day to the DMN-treated animal for four weeks. At the end of the schedule, body weight, liver weight, hydroxy proline content in the liver, and histology of the liver were estimated. However, no significant differences were found between LSKL-treated animal group and control group at any estimated points, suggesting t
hat this peptide is not effective when it is administrated perorally. The reason for its ineffectiveness is that the peptide is decomposed very easily tinder coexistence with biomaterials e.g. blood, serum, gastric juice, or intestinal juice.
3. Evaluation of antineoplastic effect of peptide LSKL using LEC rat: Peroral administration of peptide LSKL (n=3), SLLK (n=2) (1mg/1OOg BW/day) and plain water (n=2) for twenty-week-old LEC rat were started and continued for fifty-six weeks. Two of the LSKL-treated rat (6w,46w), two of the SLLK-treated rat (2w,18w), and one of the control rat (5w) were died before the completion of the study. Only two animal (LSKL, and control) could survive until 56th week. In the liver of the survived rat, multiple nodules of cancer were found and no significant differences were detected between the LSKL-treated group and other groups.
In summary, in vivo effect of the peptide LSKL on the liver damage through the inhibition of TGF-β activation was demonstrated. However, it loses the bioactivity when applied perorally because it is decomposed easily tinder coexistence with biomaterials. Therefore, organic remodeling of its bioactive molecular conformation is necessary for the clinical use. Otherwise, a different use and different way of administration. e.g. inhalation therapy for pulmonary fibrosis, can be a practical clinical application of the peptide. Less