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.
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