Mice lacking three Loci encoding 14 glutathione transferase genes: a novel tool for assigning function to the GSTP, GSTM, and GSTT families.

Glutathione S-transferases (GSTs) form a superfamily defined by their ability to catalyze the conjugation of glutathione with electrophilic substrates. These enzymes are proposed to play a critical role in protection of cellular components from damage mediated by reactive metabolites. Twenty-two cytosolic GSTs, grouped into seven families, are recognized in mice.

Allergic inflammation induces a persistent mechanistic switch in thromboxane-mediated airway constriction in the mouse.

Actions of thromboxane (TXA(2)) to alter airway resistance were first identified over 25 years ago. However, the mechanism underlying this physiological response has remained largely undefined. Here we address this question using a novel panel of mice in which expression of the thromboxane receptor (TP) has been genetically manipulated.

Role of TNFR-related 2 mediated immune responses in dextran sulfate sodium-induced inflammatory bowel disease.

Previous work has suggested that the LIGHT-TR2 costimulatory pathway plays a role in the acute and chronic stages of dextran sulfate sodium (DSS)-induced colitis [Steinberg et al. (2008); Wang et al. (2005)].

Mutation of the 5'-untranslated region stem-loop structure inhibits α1(I) collagen expression in vivo.

Type I collagen is a heterotrimeric extracellular matrix protein consisting of two α1(I) chains and one α2(I) chain. During liver fibrosis, activated hepatic stellate cells (HSCs) are the major source of the type I collagen that accumulates in the damaged tissue. Expression of α1(I) and α2(I) collagen mRNA is increased 60-fold compared with quiescent stellate cells and is due predominantly to post-transcriptional message regulation.

Nuclear factor of activated T cells negatively regulates expression of the tumor necrosis factor receptor-related 2 gene in T cells.

Tumor necrosis factor receptor-related 2 (TR2, HVEM or TNFRSF-14) plays an important role in immune responses, however, the mechanisms regulating its expression are unclear. To understand the control of TR2 gene expression, we studied the upstream region of the gene. Gel supershift assays revealed inducible binding of nuclear factor of activated T cells (NFAT) to a putative NFAT site within the TR2 promoter.

Human embryonic stem cells: a source of mast cells for the study of allergic and inflammatory diseases.

Human mast cells are tissue resident cells with a principal role in allergic disorders. Cross-linking of the high-affinity receptor for immunoglobulin E (FcepsilonRI) results in release of inflammatory mediators initiating the clinical symptoms of allergy and anaphylaxis. Much of our knowledge regarding the mechanisms of mast cell activation comes from studies of mouse bone marrow-derived mast cells.

Regulation of the murine TR2/HVEM gene expression by IRF.

TR2 (TNFR-related 2, HVEM, or TNFRSF-14), a member of the TNFR family, is involved in a number of immune responses. While TR2 is expressed on the surface of T cells during the resting state, little is known regarding how expression of the TR2 gene is regulated. To understand the mechanisms regulating the expression of TR2 in T cells, we analyzed the 5' flanking region of TR2.

Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease.

A genetic contribution to asthma susceptibility is well recognized, and linkage studies have identified a large number of genes associated with asthma pathogenesis. Recently, a locus encoding a seven-transmembrane protein was shown to be associated with asthma in founder populations. The expression of the protein GPRA (G protein-coupled receptor for asthma susceptibility) in human airway epithelia and smooth muscle, and its increased expression in a mouse model of asthma, suggested that a gain-of-function mutation in this gene increased the disease risk.

Generation of PDE4 knockout mice by gene targeting.

The development of gene-targeting techniques has ushered in a new era in mouse genetics. Two discoveries have been instrumental: the finding that an exogenous DNA introduced in mammalian cells can recombine with homologous chromosomal sequences, a process known as gene targeting, and the revelation that cultured embryonic stem (ES) cells when injected into early stage mouse embryos can contribute to produce germ-line chimeras. On the basis of these seminal findings, gene targeting by homologous recombination in mouse ES cells in vitro has been established as a powerful means of altering specific loci in the mouse genome.

Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development.

Oct4 plays an essential role in maintaining the inner cell mass and pluripotence of embryonic stem (ES) cells. The expression of Oct4 is regulated by the proximal enhancer and promoter in the epiblast and by the distal enhancer and promoter at all other stages in the pluripotent cell lineage. Here we report that the orphan nuclear receptor LRH-1, which is expressed in undifferentiated ES cells, can bind to SF-1 response elements in the proximal promoter and proximal enhancer of the Oct4 gene and activate Oct4 reporter gene expression.