FUNCTION OF GAMMA GLUTAMYL LEUKOTRIENASE

描述：谷氨酰转肽酶(GGT)和谷氨酰转氨酶 白三烯酶(GGL)，一种在申请人的实验室中鉴定的相关酶， 属于一个分解谷胱甘肽(GSH)和GSH的小基因家族 共轭关系。虽然GGT的许多生理功能是已知的，但那些 GGL的特征不是很好。申请人的实验室已经克隆了GGL， 提高了对它的抗体，并培育出具有靶向GGL突变的小鼠 (GGLtm1)。初步数据表明，GGLtm1为零突变。对于 研究的目的是，还产生了靶向GGT缺失的小鼠 突变和携带这两个基因的靶向顺式突变的小鼠。 GGL和GGT将半胱氨基白三烯(LT)C4转化为最有效的LTD4 半胱氨基LT。二肽酶包括膜结合二肽酶(MBD)的转化 LTD4到LTE4，是一个很弱的LT。半胱氨酰LTS介导血管通透性， 平滑肌收缩、嗜酸性粒细胞功能和粘液形成。这个 申请者建议研究结构、细胞定位和组织 GGL的分布，使用GGL-、GGT-和 GGL/GGT缺陷小鼠，并测试关于这些基因在 炎症和哮喘。部分阻断LTD4至TO基因的MBD缺陷小鼠 还开发了LTE4转换。描述了治疗它们的计划 使用二肽酶抑制剂，以评估LTE4‘和LTD4在心肌梗死中的作用 炎症和哮喘。这项建议的具体目标包括： 1.证明GGLtm1为零突变，并对其进行生理检测。 后果。 2.对GGL由一个轻链和一个 糖基化重链，表达于内皮细胞表面。 3.假设LTD4是主要的半胱氨酸基LT介体 炎症和中性粒细胞迁移的重要贡献者。 4.假设LTD4是主要的半胱氨酸基LT介体 患上了哮喘。

DESCRIPTION: 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.