TH transgenic mice
Tyrosine hydroxylase deficiency (THD) is a genetic neurometabolic disorder caused by
mutations in the tyrosine hydroxylase (TH) gene. TH is the rate limiting enzyme for the synthesis of dopamine, which is an important neurotransmitter that is deficient in THD. The clinical manifestations of THD are variable, ranging from early-onset lethal disease (type B) to mild Parkinson disease-like symptoms appearing in adolescence (Type A). Our group has prepared and characterized a transgenic mouce (Th-ki), with the mutation p.R203H, equivalent to the mutant p.R202H-TH1 in human, which represents a large proportion of THD patients with the serious type B form of the disease. This mouse model has been at the UiB-Animal facility, BBB, since autumn 2015.
The goal of the present application is to investigate the molecular pathogenic mechanisms of THD, type B, in the Th-ki mouse model. Furthermore, we wish to investigate and develop therapies for THD based on pharmacological chaperones and repurposing of (approved) drugs.
The pharmacological chaperones have no toxicity in cell cultures and normal mice, and the drugs have been tested before in a large number of animals, including mice, and people. For these studies we plan to use 132 homozygote Th-ki mice and a 32 wild-type controls (same sex from the same litter), as well as around 32 heterozygotes. Due to the difficulty of obtaining homozygotes and WT mice of the same sex in the same litter, we apply to breed a total of 700 animals.
Assays in cell cultures cannot totally substitute the investigation of mechanism of THD in vivo, or finally determine the efficiency of drugs, but previous investigations and evaluations in selected cell cultures - in this case dopaminergic neurons - really contribute to reduce the number of mice needed.
The transgenic Th-ki mice to be used in this project show normal survival and normal phenotype, except for a reduced motor coordination due to low TH and catecholamine content. They will be maintained in normal caging, stalling, and feeding conditions, and the procedures to be used in assessing their motor function and behaviour, and also the treatment and sampling of blood, are all classified as mildly harmful procedures.
mutations in the tyrosine hydroxylase (TH) gene. TH is the rate limiting enzyme for the synthesis of dopamine, which is an important neurotransmitter that is deficient in THD. The clinical manifestations of THD are variable, ranging from early-onset lethal disease (type B) to mild Parkinson disease-like symptoms appearing in adolescence (Type A). Our group has prepared and characterized a transgenic mouce (Th-ki), with the mutation p.R203H, equivalent to the mutant p.R202H-TH1 in human, which represents a large proportion of THD patients with the serious type B form of the disease. This mouse model has been at the UiB-Animal facility, BBB, since autumn 2015.
The goal of the present application is to investigate the molecular pathogenic mechanisms of THD, type B, in the Th-ki mouse model. Furthermore, we wish to investigate and develop therapies for THD based on pharmacological chaperones and repurposing of (approved) drugs.
The pharmacological chaperones have no toxicity in cell cultures and normal mice, and the drugs have been tested before in a large number of animals, including mice, and people. For these studies we plan to use 132 homozygote Th-ki mice and a 32 wild-type controls (same sex from the same litter), as well as around 32 heterozygotes. Due to the difficulty of obtaining homozygotes and WT mice of the same sex in the same litter, we apply to breed a total of 700 animals.
Assays in cell cultures cannot totally substitute the investigation of mechanism of THD in vivo, or finally determine the efficiency of drugs, but previous investigations and evaluations in selected cell cultures - in this case dopaminergic neurons - really contribute to reduce the number of mice needed.
The transgenic Th-ki mice to be used in this project show normal survival and normal phenotype, except for a reduced motor coordination due to low TH and catecholamine content. They will be maintained in normal caging, stalling, and feeding conditions, and the procedures to be used in assessing their motor function and behaviour, and also the treatment and sampling of blood, are all classified as mildly harmful procedures.