Transcriptomic RNAseq drug screen in cerebrocortical cultures; towards novel neurogenetic disease therapies.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA433312 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Rare monogenic diseases affect millions worldwide; although over 4,500 rare disease genotypes are known, disease-modifying drugs are available for only 5% of them. The sheer number of these conditions combined with their rarity precludes traditional costly drug discovery programs. An economically viable alternative is to repurpose established drugs for rare diseases. Many genetic diseases result from increased or decreased protein activity and identification of clinically approved drugs which moderate this pathogenic dosage holds therapeutic potential. To identify such agents for neurogenetic diseases, we have generated genome-wide transcriptome profiles of mouse primary cerebrocortical cultures grown in the presence of 218 blood brain barrier penetrant clinic-tested drugs. RNAseq and differential expression analyses were used to generate transcriptomic profiles; therapeutically relevant drug-gene interactions related to rare neurogenetic diseases identified in this fashion were further analyzed by qRT-PCR, western blot and immunofluorescence. We have created a transcriptome-wide searchable database for easy access to the gene expression data resulting from the cerebrocortical drug screen (Neuron Screen) and have mined this data to identify a novel link between thyroid hormone and expression of the peripheral neuropathy associated gene Pmp22. Our results demonstrate the utility of cerebrocortical cultures for transcriptomic drug screening, and the database we have created will foster further discovery of novel links between over 200 clinic-tested blood brain barrier penetrant drugs and genes related to diverse neurologic conditions.
2018-09-07 | GSE110256 | GEO
Project description:Complex three-dimensional (3D) in vitro model systems that recapitulate human tumor biology are essential to better understand the pathophysiology of the disease and to aid in the discovery of novel anti-cancer therapies. 3D organotypic cultures exhibit intercellula communication, nutrient and oxygen gradients, and cell polarity that is lacking in traditional two-dimensional (2D) monolayer cultures. In the present study, we could demonstrate that 2D and 3D cancer models exhibit different drug sensitivities towards both targeted inhibitors of EGFR signaling and broad acting cytotoxic agents. Changes in the kinase activities of Erb family members and differential expression of apoptosis- and survival-associated genes before and after drug treatment may account for the differential drug sensitivities. Importantly, EGFR oncoprotein addiction was evident only in the 3D cultures mirroring the effect of EGFR inhibition in the clinic. Furthermore, targeted drug efficacy was strongly increased when incorporating cancer-associated fibroblasts into the 3D cultures. Taken together, we could provide conclusive evidence that complex 3D cultures are more predictive of the clinical outcome than their 2D counterparts. In the future, 3D cultures will be instrumental for understanding the mode of action of drugs, identifying genotype-drug response relationships and developing patient-specific and personalized cancer treatments.
2017-11-30 | GSE102722 | GEO
Project description:Regulated control of gene therapies by drug induced splicing
| PRJNA736612 | ENA
Project description:Fatostatin drug treatment of mouse primary microglia cultures
| PRJNA612217 | ENA
Project description:Saracatinib drug treatment of mouse primary microglia cultures
| PRJNA612216 | ENA
Project description:Recently, three-dimensional small intestinal organoids (enteroids) have been developed from cultures of intestinal stem cells which differentiate in vitro to generate all the differentiated epithelial cell types associated with the intestine and mimic the structural properties of the intestine observed in vivo. Small-molecule drug treatment can skew organoid epithelial cell differentiation towards particular lineages, and these skewed enteroids may provide useful tools to study specific epithelial cell populations, such as goblet and Paneth cells. However, the use and characterisation of enteroid models has not yet been fully explored, such that the extent to which differentiated epithelial cell populations in these skewed enteroids represent their in vivo counterparts is not fully understood. In this study, we have performed label-free quantitative proteomics to determine whether skewing murine enteroid cultures towards the goblet or Paneth cell lineages results in changes in abundance of proteins associated with these cell lineages in vivo. Our data confirm that skewed enteroids recapitulate important features of the in vivo gut environment, confirming that they can serve as useful models for the investigation of normal and disease processes in the intestine. Furthermore, by comparison of our mass spectrometry data with histology data contained within the Human Protein Atlas, we identify putative novel markers for goblet and Paneth cells.
2019-01-11 | PXD005006 | Pride
Project description:RNA Seq datasets from HEK293 cells treated with 25nM LMI070 To date, gene therapies for human application rely on engineered promoters that cannot be finely controlled. Here, we report a universal switch element that allows precise control for gene replacement or gene silencing after exposure to a small molecule. Importantly, these small molecule inducers are in human use, are orally bioavailable when given to animals or humans, and can reach both peripheral tissues and the brain. Moreover, the switch system (Xon) does not require the co-expression of any regulatory proteins. Using Xon, translation of desired elements for controlled gene replacement or editing machinery occurs after a single oral dose, and the robustness of expression can be controlled by drug dose and with repeated drug exposure. The ability of Xon to provide temporal control of protein expression can be adapted to cell biology applications and animal studies. Additionally, due to the oral bioavailability and safety of the drugs employed, the Xon switch provides an unprecedented opportunity to refine gene therapies for more appropriate human application.
2021-07-22 | GSE176527 | GEO
Project description:Fatostatin/Saracatinib drug treatment of mouse primary microglia cultures
| PRJNA612200 | ENA
Project description:The clinical development of targeted therapies has been hampered by their limited intrinsic antitumor activity and the rapid emergence of resistance, highlighting the need to identify highly active and synergistic drug combinations. However, empirical synergistic drug screening approaches are challenging and elucidating the mechanisms that underlie such drug interactions is typically complex. Here we performed an expression based screen and network analyses to identify drugs amplyfiying the antitumor effects of NOTCH inhibition in T-ALL. These studies uncovered a novel and druggable synthetic lethal interaction between supression of protein translation and NOTCH inhibition in T-ALL. Our results illustrate the power of expression-based analyses towards the identification and functional characterization of new antitumor drug combinations for the treatment of human cancer.
2017-08-25 | GSE78188 | GEO
Project description:Variability within rare cell states enables multiple paths towards drug resistance.
| PRJNA676147 | ENA