Studies on mechanisms apoptosis and carcinogenesis of hepatocytes in hereditary liver disease and approaches for gene therapy for liver diseases

• Project/Area Number: 11470508
• Research Category: Grant-in-Aid for Scientific Research (B).
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: Kumamoto University
• Principal Investigator: ENDO Fumio Kumamoto University School of Medicine Department of Pediatrics Professor, 医学部, 教授 (00176801)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Tetsuro Kumamoto University School of Medicine Department of Pediatrics Professor, 医学部, 教授 (60112405) ; INDO Yasuhiro Kumamoto University School of Medicine Department of Hospital Assistant, 医学部・附属病院, 助手 (40244131) ; ADACHI Naoto Kumamoto University School of Medicine Department of Hospital Lecturer, 医学部・附属病院, 講師 (00264292) ; KATOH Hideki Hamamatsu Medical School Experimental Animal Institute Assistant Professor, 助教授 (30142053)
• Project Period (FY): 1999 – 2000
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥12,800,000 (Direct Cost: ¥12,800,000); Fiscal Year 2000: ¥4,800,000 (Direct Cost: ¥4,800,000); Fiscal Year 1999: ¥8,000,000 (Direct Cost: ¥8,000,000)
• Keywords: liver failure / amino acid metabolism / enzyme defect / cancer / mouse model / apoptosis / チロシン / 尿細管

Research Abstract

Hereditary tyrosinemia type I (HTI, fumarylacetoacetate hydrolase deficiency) is characterized by severe liver disease and high incidence for liver carcinomas. In this study, we investigated animal model for HT1 to elucidate mechanisms for carcinogenesis in this disease. Previously, we introduced defective HPD gene into albino lethal mice and successively rescued the phenotype. In the present study, we administered homogentisic acid which lead to liver apoptosis in these mice.
Following results are obtained.
(i) Apoptosis induced by fumarylacetoacetate in hepatocytes and renal tubular epithelial cells were prevented by the administration of caspase inhibitors.
(ii) When cell cycles were investigated, the cells injured by fumarylacetoacetate were arrested at G2M.
(iii) Recombinant adenovirus expressing human fumarylacetoacetate hydrolase prevents the liver damage and rescue the mice. In addition, recombinant adeno associated virus expressing human fumarylacetoacetate hydrolase rescues the mice.
(iv) Administration of homogentisic acid in the model mice was attempted for development of carcinoma. On histological examinatios, abnormal cells were appeared in the livers however, apparent carcinoma was not confirmed in the present study.

Research Products

• [Publications] Sun M-S.: "A mouse model of renal tubular injury of tyrosinemia type 1 : Development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in Fah/Hpd double mutant mice"J Am Soc Nephrol. 11. 291-300 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sperandeo M.P.: "Structure of the SLC7A7 Gene and Mutational Analysis of Patients Affected by Lysinuric Protein Intolerance."Am J.Hum.Genet.. 66. 92-99 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tomoeda K.: "Mutations in the 4-Hydroxyphenylpyruvic Acid Dioxygenase Gene Are Responsible for Tyrosinemia Type III and Hawkinsinuria."Molecular Genetics and Metabolism. 71. 506-510 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sun M-S.Hattori S.Kubo S.Awata H.Matsuda I.Endo F.: "A mouse model of renal tubular injury of tyrosinemia type 1 : Development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in Fah/Hpd double mutant mice."J Am Soc Nephrol.. 11. 291-300 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sperandeo M.P., Bassi M.T., Roboni M., Parenti G., Buoninconti A., Manzoni M., Incerti B., Larocca M.R, Racco M.D., Strisciuglio P., Dianzani I., Parini R, Candito M., Endo F., Ballabio A., Andria G., Sebastio G., Borsani G.: "Structure of the SLC7A7 Gene and Mutational Analysis of Patients Affected by Lysinuric Protein Intolerance."Am J.Hum.Genet.. 66. 92-99 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tomoeda K., Awata H., Matsuura T., Matsuda I., Ploechl E., Milovac T., Boneh A, Scott C.R., Danks D.M.and Endo F.: "Mutations in the 4-Hydroxyphenylpyruvic Acid Dioxygenase Gene Are Responsible for Tyrosinemia Type III and Hawkinsinuria."Molecular Genetics and Metabolism. 71. 506-510 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sperandeo M.P.: "Structure of the SLC7A7 Gene and Mutational Analysis of Patients Affected by Lysinuric Protein Intolerance."Am J.Hum.Genet.. 66. 92-99 (2000)
• [Publications] Tomoeda K.: "Mutations in the 4-Hydroxyphenylpyruvic Acid Dioxygenase Gene Are Responsible for Tyrosinemia Type III and Hawkinsinuria."Molecular Genetics and Metabolism. 71. 506-510 (2000)
• [Publications] SunM-S.: "A Mouse model of renal tubular injury of tyrosinemia type 1: Development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in Fah/Hpd double mutant mice"J Am Soc Nephrol. 11. 291-300 (2000)