Gamma-Glutamyl transpeptidase (GGT) and gamma-glutamyl leukotrienase (GGL), a related enzyme identified in the applicant's laboratory, belong to a small gene family that cleaves glutathione (GSH) and GSH conjugates. Although many of the physiologic functions of GGT are known, those of GGL not as well characterized. The applicant's laboratory has cloned GGL, raised antibodies to it, and developed mice with a targeted GGL mutation (GGLtm1). Preliminary data indicate that GGLtm1 is a null mutation. For the purposes of the study, mice have also been generated with a targeted GGT null mutation and mice carrying targeted cis mutations in both genes. GGL and GGT convert cysteinyl leukotriene (LT) C4 to LTD4, the most potent cysteinyl LT. Dipeptidases including membrane bound dipeptidase (MBD) convert LTD4 to LTE4, a very weak LT. Cysteinyl LTs mediate vascular permeability, smooth muscle contraction, eosinophil function and mucus formation. The applicant proposes to study the structure, cellular localization, and tissue distribution of GGL, assess its function by using GGL-, GGT-, and GGL/GGT-deficient mice, and test hypotheses about the role of these genes in inflammation and asthma. MBD-deficient mice with a partial block in LTD4 to LTE4 conversion have also been developed. Plans are described to treat them with a dipeptidase inhibitor in order to assess LTE4' and LTD4 role in inflammation and asthma.
Specific Aims of this proposal include: 1. Demonstration that GGLtml is a null mutation and to examine its physiologic consequences. 2. Testing of the hypothesis that GGL consists of a light chain and a glycosylated heavy chain and is expressed on the surface of endothelial cells. 3. Testing of the hypotheses that LTD4 is the principal cysteinyl LT mediator of inflammation and a significant contributor to neutrophil migration. 4. Testing of the hypothesis that LTD4 is the principal cysteinyl LT mediator of bronchial asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES007827-06
Application #
6285035
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Thompson, Claudia L
Project Start
1996-03-01
Project End
2006-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
6
Fiscal Year
2001
Total Cost
$337,875
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Chavez, Jaime; Young, Hays W J; Corry, David B et al. (2006) Interactions between leukotriene C4 and interleukin 13 signaling pathways in a mouse model of airway disease. Arch Pathol Lab Med 130:440-6
Levasseur, Regis; Barrios, Roberto; Elefteriou, Florent et al. (2003) Reversible skeletal abnormalities in gamma-glutamyl transpeptidase-deficient mice. Endocrinology 144:2761-4
Rojas, E; Shi, Z-Z; Valverde, M et al. (2003) Cell survival and changes in gene expression in cells unable to synthesize glutathione. Biofactors 17:13-9
Pardo, Annie; Ruiz, Victor; Arreola, Jose Luis et al. (2003) Bleomycin-induced pulmonary fibrosis is attenuated in gamma-glutamyl transpeptidase-deficient mice. Am J Respir Crit Care Med 167:925-32
Han, Bing; Luo, Guoyang; Shi, Zheng-Zheng et al. (2002) Gamma-glutamyl leukotrienase, a novel endothelial membrane protein, is specifically responsible for leukotriene D(4) formation in vivo. Am J Pathol 161:481-90
Shi, Z Z; Han, B; Habib, G M et al. (2001) Disruption of gamma-glutamyl leukotrienase results in disruption of leukotriene D(4) synthesis in vivo and attenuation of the acute inflammatory response. Mol Cell Biol 21:5389-95
Barrios, R; Shi, Z Z; Kala, S V et al. (2001) Oxygen-induced pulmonary injury in gamma-glutamyl transpeptidase-deficient mice. Lung 179:319-30
Chevez-Barrios, P; Wiseman, A L; Rojas, E et al. (2000) Cataract development in gamma-glutamyl transpeptidase-deficient mice. Exp Eye Res 71:575-82
Rojas, E; Valverde, M; Kala, S V et al. (2000) Accumulation of DNA damage in the organs of mice deficient in gamma-glutamyltranspeptidase. Mutat Res 447:305-16
Kumar, T R; Wiseman, A L; Kala, G et al. (2000) Reproductive defects in gamma-glutamyl transpeptidase-deficient mice. Endocrinology 141:4270-7

Showing the most recent 10 out of 21 publications