Filters
Technology
Platform
SRP055930
Mus musculus
6 Downloadable Samples
Illumina HiSeq 1000
Description
Pulmonary fibrosis (PF) is associated with many chronic lung diseases including Systemic sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF) and Cystic Fibrosis (CF) which are characterized by the progressive accumulation of stromal cells and formation of scar tissue. Pulmonary fibrosis is a dysregulated response to alveolar injury which causes a progressive decline in lung function and refractory to current pharmacological therapies. Airway and alveolar epithelial cells and stromal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Recent animals models generated in our lab demonstrate clinical phenotypes seen in human fibrotic disease. The mouse model of transforming growth factor-a (TGFa)-induced fibrosis include conditionally expressing TGFa in the lung epithelium under control of the CCSP promoter driving rtTA expression (CCSP/TGFa). This allow the TGFa is only expressed in airway and alveolar epithelial cells and only when mice fed doxycycline (Dox). Similar to PF in humans, TGFa mice on Dox developed a progressive and extensive adventitial, interstitial and pleural fibrosis with a decline in lung mechanics. Thus, the TGFa transgenic mouse is a powerful model to determine lung cell-specific molecular signatures involved in pulmonary fibrosis. In this study, we sought to determine changes in the transcriptome during TGFa-induced pulmonary fibrosis. Our results showed that several pro-fibrotic genes increased in the lungs of TGFa mice. This study demonstrates that WT1 network gene changes associated with fibrosis and myfibroblast accumulation and thus may serve as a critical regulator fibrotic lung disease. Overall design: mRNA profiles of CCSP/- and CCSP/TGFalpha mice treated with Dox
Publication Title
Fibrocytes Regulate Wilms Tumor 1-Positive Cell Accumulation in Severe Fibrotic Lung Disease.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 1000
Description
Interleukin-31 (IL-31), a T cells derived cytokine which is mainly produced by CD4+ T cells skewed towards Th2 phenotypes. It signals via a heterodimeric receptors composed of IL-31RA and OSMR that is expressed constitutively in epithelial cells and keratinocytes. IL-31 is shown to play a pathogenic role in allergic and inflammatory diseases. Transgenic mice overexpressing IL-31 have a phenotype similar to atopic dermatitis. Here, we studied the role of IL-31 in skin damage by intradermal administration of recombinant IL-31. Notably, IL-31 was sufficient to increase epidermal basal cell proliferation and thickening of the epidermal layer of skin in mice. Analysis of skin transcriptome indicates a significant increase in the transcripts involved in epidermal cell proliferation and pathological skin remodeling. Thus, our study revealed an important role of IL-31 signaling in activating transcriptional programs involved in the pathophysiology of skin diseases. Overall design: mRNA profiles of C57BL/6 mice skin injected with saline and rIL-31 (20µg) via i.d.
Publication Title
IL-31-Driven Skin Remodeling Involves Epidermal Cell Proliferation and Thickening That Lead to Impaired Skin-Barrier Function.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 20 Downloadable Samples
- Illumina HiSeq 1000
Description
Pulmonary fibrosis is often triggered by an epithelial injury resulting in the formation of fibrotic lesions in the lung, which progress to impair gas exchange and ultimately cause death. Recent clinical trials using drugs that target either inflammation or a specific molecule have failed, suggesting that multiple pathways and cellular processes need to be attenuated for effective reversal of established and progressive fibrosis. Although activation of MAPK and PI3K pathways have been detected in human fibrotic lung samples, the therapeutic benefits of in vivo modulation of the MAPK and PI3K pathways in combination are unknown. Overexpression of TGFa in the lung epithelium of transgenic mice results in the formation of fibrotic lesions similar to those found in human pulmonary fibrosis, and previous work from our group shows that inhibitors of either the MAPK or PI3K pathway can alter the progression of fibrosis. In this study, we sought to determine whether simultaneous inhibition of the MAPK and PI3K signaling pathways is a more effective therapeutic strategy for established and progressive pulmonary fibrosis. Our results showed that inhibiting both pathways had additive effects compared to inhibiting either pathway alone in reducing fibrotic burden, including reducing lung weight, pleural thickness, and total collagen in the lungs of TGFa mice. This study demonstrates that inhibiting MEK and PI3K in combination abolishes proliferative gene changes associated with fibrosis and myfibroblast accumulation and thus may serve as a therapeutic option in the treatment of human fibrotic lung disease where these pathways play a role. Overall design: mRNA profiles of CCSP/TGFalpha mice treated with vehicle, ARRY, PX-866, ARRY/PX-866
Publication Title
Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
Cancer cell motility and invasiveness are fundamental characteristics of the malignant phenotype and are regulated through diverse signaling networks involving kinases and transcription factors. In this study, we identify a nuclear hormone receptor (ER)-protein kinase (ERK5)-cofilin (CFL1) network that specifies the degree of breast cancer cell aggressiveness through coupling of actin reorganization and hormone receptor-mediated transcription. Using dominant negative and constitutively active forms, as well as small molecule inhibitors of ERK5 and MEK5, we show that hormone activation of estrogen receptor- determines the nuclear versus cytoplasmic localization of the MAPK family member ERK5, which functions as a coregulator of ER-gene transcription.
Publication Title
Novel roles for ERK5 and cofilin as critical mediators linking ERα-driven transcription, actin reorganization, and invasiveness in breast cancer.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 30 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
The nuclear hormone receptor, estrogen receptor-alpha (ER), and MAP kinases both play key roles in hormone-dependent cancers, yet their interplay and the integration of their signaling inputs remain poorly understood. In these studies, we document that estrogen-occupied ER activates and interacts with ERK2, a downstream effector in the MAPK pathway, resulting in ERK2 and ER colocalization at chromatin binding sites across the genome of breast cancer cells.
Publication Title
Genomic collaboration of estrogen receptor alpha and extracellular signal-regulated kinase 2 in regulating gene and proliferation programs.
Sample Metadata Fields
Disease, Disease stage, Cell line, Time
View Samples- Mus musculus
- 23 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Exposure to ultraviolet (UV) irradiation is the major cause of nonmelanoma skin cancer, the most common form of cancer in the United States. UV irradiation has a variety of effects on the skin associated with carcinogenesis, including DNA damage and effects on signal transduction. The alterations in signaling caused by UV regulate inflammation, cell proliferation, and apoptosis. UV also activates the orphan receptor tyrosine kinase and proto-oncogene Erbb2 (HER2/neu). In this study, we demonstrate that the UV-induced activation of Erbb2 regulates the response of the skin to UV. Inhibition or knockdown of Erbb2 before UV irradiation suppressed cell proliferation, cell survival, and inflammation after UV. In addition, Erbb2 was necessary for the UV-induced expression of numerous proinflammatory genes that are regulated by the transcription factors nuclear factor-kappaB and Comp1, including interleukin-1beta, prostaglandin-endoperoxidase synthase 2 (Cyclooxygenase-2), and multiple chemokines. These results reveal the influence of Erbb2 on the UV response and suggest a role for Erbb2 in UV-induced pathologies such as skin cancer.
Publication Title
Erbb2 regulates inflammation and proliferation in the skin after ultraviolet irradiation.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 7 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The transcription factor FOXM1 coordinates the expression of cell cycle-related genes and plays a pivotal role in tumorigenesis and cancer progression. We have previously shown that FOXM1 acts downstream of 14-3-3 signaling, which correlates with a more aggressive tumor phenotype. However, the role that FOXM1 might play in engendering the resistance to endocrine treatments in estrogen receptor-positive (ER+) patients when tumor FOXM1 is high, has not been clearly defined.
Publication Title
The forkhead transcription factor FOXM1 promotes endocrine resistance and invasiveness in estrogen receptor-positive breast cancer by expansion of stem-like cancer cells.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Integrative genomics of gene and metabolic regulation by estrogen receptors α and β, and their coregulators.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 10 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective new approach to treating prostate cancer. Here we provide proof-of-concept that a small molecule inhibitor of nuclear ß-catenin activity (called C3) can inhibit both the AR and ß-catenin signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both ß-catenin/TCF and ß-catenin/AR protein interaction, reflecting the fact that TCF and AR have overlapping binding sites on ß-catenin. Given that AR interacts with, and is transcriptionally regulated by ß-catenin, C3 treatment also resulted in decreased occupancy of ß-catenin on the AR promoter and diminished AR and AR/ß-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and ß-catenin cofactor, CARM1, providing new insight into the unrecognized function of ß-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model, and blocked renewal of bicalutamide-resistant sphere forming cells, indicating the therapeutic potential of this approach. Overall design: Compare and contrast the expression profile of prostate cancer cells treated with a Wnt inhibitor (C3) with respect to ß-catenin and AR knockdown (all samples in duplicates).
Publication Title
Inhibition of androgen receptor and β-catenin activity in prostate cancer.
Sample Metadata Fields
Disease, Subject
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
The closely related transcription factors (TFs), estrogen receptors ER and ER, regulate divergent gene expression programs and proliferative outcomes in breast cancer. Utilizing MCF-7 breast cancer cells with ER, ER, or both receptors as a model system to define the basis of differing response specification by related TFs, we show that these TFs and their key coregulators, SRC3 and RIP140, generate overlapping as well as unique chromatin-binding and transcription-regulating modules.
Publication Title
Integrative genomics of gene and metabolic regulation by estrogen receptors α and β, and their coregulators.
Sample Metadata Fields
Specimen part, Cell line
View Samples