Abstract

The hypothesis is that individuals carrying mutations in the genes coding for antioxidant enzymes will be predisposed to diseases whose pathogenesis is associated with an unbalanced production of oxygen radicals. The overall goal of this grant is to define the critical role of each antioxidant enzyme and the balance among antioxidant enzymes in pulmonary defense against oxidant injury. There are two aims. The first is to generate mouse models deficient for four antioxidant enzymes: CuZnSOD, MnSOD, GSHPx and catalase. Mice heterozygous for the targeted mutations will be used in breeding to determine the feasibility of generating homozygous knockout mice. Pathological studies will look for potential gross or subtle abnormalities in the genetically mutated mice. RNA and protein content for each of the antioxidant enzymes will be measured in various tissues including lung of normal heterozygous and homozygous mice.
The second aim i s to define biochemically and morphologically whether deficiencies in the antioxidant enzymes will render animals more susceptible to lung injury induced by hyperoxia, bleomycin, and asbestos.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056421-02
Application #
2460199
Study Section
Special Emphasis Panel (ZRG2-RAP (01))
Project Start
1996-08-01
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Wayne State University
Department
Type
Organized Research Units
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202

  Publications

Johnson, Robert M; Ho, Ye-Shih; Yu, Dae-Yeul et al. (2010) The effects of disruption of genes for peroxiredoxin-2, glutathione peroxidase-1, and catalase on erythrocyte oxidative metabolism. Free Radic Biol Med 48:519-25
Johnson, Robert M; Goyette Jr, Gerard; Ravindranath, Y et al. (2005) Hemoglobin autoxidation and regulation of endogenous H2O2 levels in erythrocytes. Free Radic Biol Med 39:1407-17
Kasahara, Emiko; Lin, Li-Ren; Ho, Ye-Shih et al. (2005) SOD2 protects against oxidation-induced apoptosis in mouse retinal pigment epithelium: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci 46:3426-34
Ho, Ye-Shih; Xiong, Ye; Ma, Wanchao et al. (2004) Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. J Biol Chem 279:32804-12
Bajt, Mary Lynn; Ho, Ye-Shih; Vonderfecht, Steven L et al. (2002) Reactive oxygen as modulator of TNF and fas receptor-mediated apoptosis in vivo: studies with glutathione peroxidase-deficient mice. Antioxid Redox Signal 4:733-40
Johnson, Robert M; Goyette Jr, Gerard; Ravindranath, Yaddanapudi et al. (2002) Oxidation of glutathione peroxidase-deficient red cells by organic peroxides. Blood 100:1515-6
Strayer, Marlene; Savani, Rashmin C; Gonzales, Linda W et al. (2002) Human surfactant protein B promoter in transgenic mice: temporal, spatial, and stimulus-responsive regulation. Am J Physiol Lung Cell Mol Physiol 282:L394-404
Reddy, V N; Giblin, F J; Lin, L R et al. (2001) Glutathione peroxidase-1 deficiency leads to increased nuclear light scattering, membrane damage, and cataract formation in gene-knockout mice. Invest Ophthalmol Vis Sci 42:3247-55
Yoshida, T; Maulik, N; Ho, Y S et al. (2001) H(mox-1) constitutes an adaptive response to effect antioxidant cardioprotection: A study with transgenic mice heterozygous for targeted disruption of the Heme oxygenase-1 gene. Circulation 103:1695-701
Chen, Z; Chua, C C; Ho, Y S et al. (2001) Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. Am J Physiol Heart Circ Physiol 280:H2313-20

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