Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). However, understanding its pathogenesis has been hindered by lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with targeted CFTR genes. We now report that within months of birth, CF pigs spontaneously develop hallmark features of CF lung disease including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting an equal opportunity host defense defect. In humans, the temporal and/or causal relationships between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation, but were less often sterile than controls. Moreover, after intrapulmonary bacterial challenge, CF pigs failed to eradicate bacteria as effectively as wild- type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Finding that CF pigs have a bacterial host defense defect within hours of birth provides an exciting opportunity to further investigate pathogenesis and to test therapeutic and preventive strategies before secondary consequences develop.
Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth.
Specimen part
View SamplesPreterm birth is an important unsolved clinical problem. Despite advanced treatments, infants who survive prematurity remain at increased risk for permanent disabilities. In approximately one-third of cases, prematurity is related to infection and/or inflammation, which renders hostile the normally receptive intrauterine environment. Proinflammatory cytokines provoke up-regulation of genes that promote uterine contractions. Using monolayer cultures of human decidual cells as a model, we profiled the global pattern of gene expression in response to cytokine challenge.
Inflammatory gene networks in term human decidual cells define a potential signature for cytokine-mediated parturition.
Specimen part, Time
View SamplesPremature birth continues to be a challenging pregnancy complication, and a body of literature indicates that inflammation can contribute to premature delivery by converting a receptive uterine environment to a hostile one. Cytokines have been demonstrated to provoke up-regulation of inflammatory genes (e.g. interleukin-1, 6, and 8, tumor necrosis factor-alpha, cyclooxygenase-2, and microsomal prostaglandin E synthase-1).
Inflammatory gene regulatory networks in amnion cells following cytokine stimulation: translational systems approach to modeling human parturition.
Specimen part, Time
View SamplesGrainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMTs) occurring in wound healing processes and the cancer stem cell-like compartment of tumors, including TGF--dependence, we investigated the role of a Grainyhead gene (GRHL2) in oncogenic EMT. Grainyhead was specifically down-regulated in the claudin-low subclass of mammary tumors and in the basal-B subclass of breast cancer cell lines. Functionally, GRHL2 suppressed TGF--induced, Twist-induced or spontaneous EMT, enhanced anoikis-sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated, in part, by its suppression of ZEB1 expression, through direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription, and up-regulated mir200b/c as well as the TGF- receptor antagonist, BMP2. The expression of GRHL2 in the breast cancer cell line MDA-MB-231 triggered a mesenchymal-to-epithelial transition and sensitized the cells to anoikis. These results indicate that GRHL2 is a suppressor of the oncogenic EMT.
Suppression of the epithelial-mesenchymal transition by Grainyhead-like-2.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Altered compensatory cytokine signaling underlies the discrepancy between <i>Flt3<sup>-/-</sup></i> and <i>Flt3l<sup>-/-</sup></i> mice.
Specimen part
View SamplesThe goal of this study was to determine whether there are any gene expression changes in cDC1s and cDC2s from WT, Flt3 KO, or Flt3L KO mice. Specifically whether developing in the absence of Flt3 signaling had any effects on the gene expression of the cDCs
Altered compensatory cytokine signaling underlies the discrepancy between <i>Flt3<sup>-/-</sup></i> and <i>Flt3l<sup>-/-</sup></i> mice.
Specimen part
View SamplesTo determine any expresssion changes in cDC2s from WT and CD11c-Cre Notch2f/f mice immunized with sheep red blood cells
Notch2-dependent DC2s mediate splenic germinal center responses.
Specimen part
View SamplesThe goal of this study was to determine whether there are any gene expression changes in pDCs from WT and Flt3 KO mice. Specifically whether developing in the absence of Flt3 signaling had any effects on the gene expression of the pDCs
Altered compensatory cytokine signaling underlies the discrepancy between <i>Flt3<sup>-/-</sup></i> and <i>Flt3l<sup>-/-</sup></i> mice.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
<i>Airn</i> Regulates Igf2bp2 Translation in Cardiomyocytes.
Specimen part
View SamplesTo elucidate the function of Airn isoforms in the heart, we conducted RNA immunoprecipitation experiment followed by microarray (RIP-chip) in murine cardiomoycyte cell line HL-1.
<i>Airn</i> Regulates Igf2bp2 Translation in Cardiomyocytes.
Specimen part
View Samples