Aims: While Huntingtons disease is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model.
Cardiac Dysfunction in the BACHD Mouse Model of Huntington's Disease.
Specimen part, Disease, Disease stage
View SamplesGene expression analysis, a) comparing isogenic karyotypically normal iPSCs to del7q-iPSCs, b) comparing del7q-iPSCs to spontaneously corrected iPSCs. The chr7q deletion results in reduced expression levels of a large number of genes in the chr7q deleted region
Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells.
Specimen part, Cell line
View SamplesSnail is a zinc-finger transcription factor best known for its ability to down-regulate E-cadherin. Its established significance in embryology and organogenesis has been expanded to include a role in the tumor progression of a number of human cancers. In addition to E-cadherin, it has more recently been associated with the down-regulation and up-regulation of a number of other genes that affect important malignant phenotypes.
Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma.
Cell line
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells.
Age, Specimen part
View SamplesLung cancers are documented to have remarkable intratumoral genetic heterogeneity. However, little is known about the heterogeneity of biophysical properties, such as cell motility, and its relationship to early disease pathogenesis and micrometastatic dissemination. In this study, we identified and selected a subpopulation of highly migratory premalignant pulmonary epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of unselected cells. This enhanced migratory capacity was found to be Rac1-dependent and heritable, as evidenced by maintenance of the phenotype through multiple cell divisions continuing more than 8-weeks post-selection. The morphology of this lung epithelial subpopulation was characterized by increased cell protrusion intensity. In a murine model of micrometastatic seeding and pulmonary colonization, the motility-selected premalignant cells exhibit both enhanced survival in short term assays and enhanced outgrowth of premalignant lesions in longer term assays, thus overcoming important aspects of metastatic inefficiency. Overall, our findings indicate that among premalignant pulmonary epithelial cells, subpopulations with heritable motility-related biophysical properties exist, and these may explain micrometastatic seeding occurring early in the pathogenesis of lung cancer. Understanding, targeting, and preventing these critical biophysical traits and their underlying molecular mechanisms may provide a new approach to prevent metastatic behavior.
Identification of a Human Airway Epithelial Cell Subpopulation with Altered Biophysical, Molecular, and Metastatic Properties.
Age, Specimen part
View SamplesAmong the dendritic cell (DC) subsets, plasmacytoid DCs are thought to be important in both generating antiviral and antitumor responses. These cells may be useful in developing dendritic cell-based tumor vaccines, however, the rarity of these cells in the peripheral blood have hampered attempts to understand their biology. To provide better insight into the biology of plasmacytoid DCs, we isolated these cells from the peripheral blood of healthy donors in order to further characterize their gene expression. Using gene array technology we compared the genetic profiles of these cells to those of CD14+ monocytes isolated from the same donors and found several immune related genes upregulated in this cell population. Understanding the genetic profiles of this dendritic cell subtype as well as others such as the BDCA-1 expressing myeloid DCs may enable us to manipulate these cells ex-vivo to generate enhanced DC-based tumor vaccines inducing more robust antitumor responses.
Genetic profiles of plasmacytoid (BDCA-4 expressing) DC subtypes-clues to DC subtype function in vivo.
No sample metadata fields
View SamplesPitx3 is a transcription factor that is expressed in all midbrain dopaminergic (mDA) neurons during early development, but later becomes restricted in dopaminergic subsets of substantia nigra compacta (SNc) and of the ventral tegmental are (VTA) that are vulnerable to neurodegenerative stress (MPTP, 6-OHDA, rotenone, Parkinson's disease). Overall, in mice, Pitx3 is required for developmental survival of ventral SNc neurons and for postnatal survival of VTA neurons (after postnatal day 40). With the aim of determining the gene networks that distinguish Pitx3-vulnerable (Pitx3-positive) from Pitx3-resistant (Pitx3-negative) subsets of SNc and VTA, we performed a comparison at the transcriptome level between FAC-sorted mDA neurons of SNc and VTA that were obtained from wild-type and Pitx3-/- newborn mice. The latter mice have already lost the majority of their TH+Calb1- mDA neurons of ventral SNc (Pitx3-dependent), but their TH+Calb1+ neurons of dorsal SNc (Pitx3-independent), including all of VTA neurons (50% are Pitx3-dependent and 50% Pitx3-independent), are unaffected by Pitx3 deletion. At postnatal day 40, Pitx3-/- mice display a marked loss of dopaminergic subsets of VTA that normally co-express Pitx3 and Calb1 (Pitx3-dependent neurons of VTA).
Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra.
Specimen part
View SamplesWe have discovered subsets of axon guidance molecules and transcription factors that are enriched in specific subsets of olfactory sensory neurons. We have demonstrated guidance activity for three of the candidate axon guidance genes we identified, suggesting that this approach is an efficient method for characterizing guidance systems relevant to olfactory axon targeting. Overall design: Single-cell RNASeq of OMP-expressing olfactory sensory neurons was performed by capture on Fluidigm-C1 followed by sequencing on Illumina HiSeq2500
Coordination of olfactory receptor choice with guidance receptor expression and function in olfactory sensory neurons.
No sample metadata fields
View SamplesPseudomonas aeruginosa is a re-emerging opportunistic pathogen with broad antimicrobial resistance. We have previously reported that the major siderophore pyoverdine from this pathogen disrupts mitochondrial networks and induces a lethal hypoxic response in model host Caernorhabditis elegans. However, the mechanism of such cytotoxicity remained unclear. Here, we demonstrate that pyoverdine translocates into host cells, binding to host ferric iron sources. The reduction of host iron content disrupts mitochondrial function such as NADH oxidation and ATP production and activates mitophagy. This activates a specific immune response that is distinct from colonization-based pathogensis and exposure to downstream pyoverdine effector Exotoxin A. Host response to pyoverdine resembles that of a hypoxic crisis or iron chelator treatment. Furthermore, we demonstrate that pyoverdine is a crucial virulence factor in P. aerguinosa pathogenesis against cystic fibrosis patients; F508 mutation in human CFTR increases susceptibility to pyoverdine-mediated damage.
Pyoverdine, a siderophore from Pseudomonas aeruginosa, translocates into C. elegans, removes iron, and activates a distinct host response.
Specimen part, Treatment
View SamplesBackground: COPD is currently the fourth leading cause of death worldwide and predicted to rank third by 2020. Statins are commonly used lipid lowering agents with documented benefits on cardiovascular morbidity and mortality, and have also been shown to have pleiotropic effects including anti-inflammatory and anti-oxidant activity. Objective: Identify a gene signature associated with statin use in the blood of COPD patients, and identify molecular mechanisms and pathways underpinning this signature that could explain any potential benefits in COPD. Methods: Whole blood gene expression was measured on 168 statin users and 452 non-users from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study. Gene expression was measured using the Affymetrix Human Gene 1.1 ST microarray chips. Factor Analysis for Robust Microarray Summarization (FARMS) was used to process the expression data and to filter out non-informative probe sets. Differential gene expression analysis was undertaken using the Linear Models for Microarray data (Limma) package adjusting for propensity score and employing a surrogate variable analysis. Similarity of the expression signal with published gene expression profiles was performed in ProfileChaser. Results: 18 genes were differentially expressed between statin users and non-users at a false discovery rate of 10%. Top genes included LDLR, ABCA1, ABCG1, MYLIP, SC4MOL, and DHCR24. The 18 genes were significantly enriched in pathways and biological processes related to cholesterol homeostasis and metabolism, and were enriched for transcription factor binding sites for sterol regulatory element binding protein 2 (SREBP-2). The resulting gene signature showed correlation with Huntington disease, Parkinsons disease and acute myeloid leukemia. Conclusion: Statins gene signature was not enriched in any pathways related to respiratory diseases, beyond the drugs effect on cholesterol homeostasis.
The Effect of Statins on Blood Gene Expression in COPD.
Sex, Age, Disease
View Samples