CREATION AND ANALYSIS OF A MOUSE MODEL OF TYROSINEMIA

Project: Research project

Project Details

Description

Tyrosinemia type I is an autosomal recessive metabolic disease caused by
deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). Its main
clinical features include progressive liver failure, renal tubular
damage, neurologic crisis and the development of liver cancer.
Biochemically the disease is characterized by the accumulation of toxic
metabolites such as succinyl acetone, but also multiple secondary
abnormalities in liver metabolism such as decreased tyrosine amino
transferase (TAT) and elevated alpha-fetoprotein (AFP). The mortality
rate is high despite dietary therapy and death usually occurs in
childhood unless liver transplantation is performed. However, an
adequate animal model in which to test therapeutic strategies and to
study the disease pathophysiology is not available. We have used homologous recombination in embryonic stem cells to disrupt
exon 5 of the murine FAH gene and have created mice heterozygous for this
FAHexon5 mutation. In this application we propose to carry out the
phenotypic and biochemical characterization of animals homozygous for
FAHexon5. Should the new mouse strain prove to not represent an adequate
model of the human mutations into the FAHexon5 background. Mutations in
human tyrosinemia I patients will be identified and characterized for
this purpose. We will use the FAH deficient mice to test dietary and pharmacological
treatments for the disorders. We will focus our efforts on using
inhibitors of homogentisic acid oxidase to refuse the production of toxic
metabolites and to ameliorate the cellular damage caused by the disease.
StatusFinished
Effective start/end date12/1/9312/31/17

Funding

  • National Institutes of Health: $369,057.00
  • National Institutes of Health: $368,829.00
  • National Institutes of Health: $308,500.00
  • National Institutes of Health: $342,200.00
  • National Institutes of Health: $290,942.00
  • National Institutes of Health
  • National Institutes of Health: $342,337.00
  • National Institutes of Health
  • National Institutes of Health: $266,254.00
  • National Institutes of Health: $359,910.00
  • National Institutes of Health: $282,468.00
  • National Institutes of Health: $175,908.00
  • National Institutes of Health: $327,348.00
  • National Institutes of Health: $314,796.00
  • National Institutes of Health: $324,198.00
  • National Institutes of Health: $217,235.00
  • National Institutes of Health: $327,642.00
  • National Institutes of Health: $397,238.00
  • National Institutes of Health: $175,836.00
  • National Institutes of Health: $274,242.00
  • National Institutes of Health
  • National Institutes of Health: $230,463.00

ASJC

  • Medicine(all)

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