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Genetic Studies
Project Summary

Title: Do Defective Gpx1 and ALDH2 Genes Increase Sensitivity to Environmental Exposure
Synopsis: The objective of this study is to determine whether susceptibility to environmental exposure may result from defects in the expression of certain gene products.
Overall Project Objective: We propose to test the hypothesis that susceptibility to environmental exposure may result from defects in the expression of gene products that prevent and/or repair damage from lipid peroxidation in the mitochondrial membrane.
Status/Results to Date: Update: One of the specific aims of this project was to develop a mouse model with a targeted deletion of the mitochondrial aldehyde dehydrogenase (ALDH2) gene to test the hypothesis that reduction in the capacity to remove biogenic aldehydes increases vulnerability to environmental exposure to paraquat and ionizing radiation. Through a contract with Lexicon Genetics in Woodlands, Texas we have made a mouse with a targeted deletion of the ALDH2 gene. This is the first ALDH2 knockout mouse to be produced by any laboratory. We are now beginning to breed the breeding pairs for the wild-type and knockout mice. In addition to the specific aims outlined above, we also plan to determine whether the ALDH2 gene knockout predisposes mice to development of the pathological changes characteristic of Parkinson's disease following exposure to the insecticide rotenone. Recent studies in cell culture suggest that rotenone causes increases in the neurotoxic metabolite of dopamine dihydroxyphenylacetic acid (DOPAL). A pharmacological inhibitor of ALDH2 potentiated the increase in DOPAL and in cell death. We plan to use a combination of histochemical and neurochemical assays to determine whether the combination of the ALDH2 knockout and rotenone exposure potentiates cell death in vivo.
Project:VA-65D
Agency:Department Of Veterans' Affairs
Location:San Antonio Environmental
P.I. Name:Randy Strong, Ph. D.
Research Type:Mechanistic
Research Focus:Environmental Toxicology
Focus Category:Genetic Studies
Status:Ongoing
Study Start Date:January 07,2000
Estimated Completion Date:January 07,2005
Specific Aims: (1) To use mice homozygous and heterozygous for a targeted deletion of the glutathione peroxidase gene to test the hypothesis that deficiency in glutathione peroxidase increases sensitivity to long-term, low-level environmental exposure to hazards that promote lipid peroxidation, specifically paraquat and ionizing radiation. Dependent variables will be length of survival, tissue-specific pathology, changes in membrane products of lipid peroxidation, protein oxidation and DNA damage. (2) To develop a mouse model with a targeted deletion of the mitochondrial aldehyde dehydrogenase gene to test the hypothesis that reduction in the capacity to remove biogenic aldehydes increases vulnerability to environmental exposure to paraquat and ionizing radiation. Initial characterization of this animal model will include tissue pathology and survival. If the homozygous null mutation is not lethal, then animals homozygous and heterozygous for the mutation will be assessed for sensitivity to paraquat and ionizing radiation. Vulnerability to environmental exposure will be as described in specific objective 1. (Years I and 2) (3) To test the hypothesis that deficiencies in both mitochondrial glutathione peroxidase and aldehyde dehydrogenase increase the vulnerability to environmental exposure. Mice with a targeted deletion of the mitochondrial aldehyde dehydrogenase will be bred to mice with a targeted deletion of the glutathione peroxidase gene. Survival, tissue pathology, protein oxidation, membrane lipid peroxidation and DNA damage will be measured. (Year 3).
Methodology: See Specific Aims.
Most Recent Publications:

Foster D, Strong R, Morgan WW. A tetracycline-repressible transactivator approach suggests a shorter half-life for tyrosine hydroxylase mRNA. Brain Res, 7(2):137-46, Jun 2001. Abstract

Fernandez E, Yu R, Corbitt J, Strong R. Age-related increases in rat adrenal tyrosine hydroxylase gene expression occur at the post-transcriptional level: Evidence for a role of the tyrosine hydroxylase messenger RNA 3' untranslated region. Journal of Neurochem, In revision. Article

Hagerty T, Elango N, Morgan WW, Strong R. Identification of a glucocorticoid-responsive element in the promoter region of the mouse tyrosine hydroxylase gene. Journal of Neurochem, 76(3):825-34, Feb 2001. Abstract

Hagerty T, Fernandez E, Lynch K, Wang S, Morgan WW, Strong R. Interaction of a glucocorticoid-responsive element with regulatory sequences in the promoter region of the mouse tyrosine hydroxylase gene. Journal of Neurochem, 78(6):1379-88, Sep 2001. Abstract

Corbitt J, Hagerty T, Fernandez E, Morgan WW, Strong R. Two PACAP1 receptor agonists differentially regulate post-transcriptional elevation of tyrosine hydroxylase messenger RNA in PC12 cells: the role of protein kinase C. Neuropeptides, In Press. Article

Basiboina R, Haycock JW, Corbitt J, Vivekananda J, Strong R. Tyrosine hydroxyiase gene expression in the rat adrenal gland: Age-elated changes at the level of translation. Mol Brain Res, Submitted. Article