Induced pluripotent stem cell modeling of patients and drugs at risk for QT prolongation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA671350 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Modeling long QT syndrome using gene-edited pigs
| PRJNA1216026 | ENA
Project description:Liver disease and toxicity that causes impaired liver functionality have severe effects on normal body functions. There is a strong need for better and more predictable in vitro models for studying disease and improving mechanistic understanding of adverse effects of drugs in humans. This experiment aimed to characterize human induced pluripotent stem cell-derived hepatocytes (hiPS-HEP), in order to assess their potential as in vitro tools for metabolism studies and disease modeling. hiPS-HEP from three cell lines were compared to human primary hepatocytes from three donors, before and after plating.
2020-02-06 | E-MTAB-8286 | biostudies-arrayexpress
Project description:To date, KCNH2 mutations identified in LQT2 patients have been heavily studied by heterologous expression systems, allowing for pathogenicity evaluation of a certain hERG mutation by overexpressing mutant channels. However, they fall short in mimicking the full spectrum of electrophysiological changes and ion channel remodeling that occur in cardiomyocytes under physiological conditions in the context of LQT. Due to the marked differences in the lifespan, size, anatomy and physiology from humans, current zebrafish and rodent models cannot fully mimic the abnormal QT interval diseases 2. For instance, rodents exhibit an extremely higher heart rate and a much shorter action potential duration (APD) compared to humans. IKr is the predominant repolarizing current in human ventricles while inhibition of IKr in rodents has no significant effect on ventricular repolarization, making it infeasible to study LQT2 by genetic mouse model 3. Hence, there is a crucial need to construct an animal model capable of mimicking human inherited arrhythmia conditions. To address the above scientific question, we chose to create a miniature pig model. Given many physiological similarities with humans, and breeding and genome editing advantages (when compared to non-human primates), To explore the mechanism underlying mutation of KCNH2 caused LQT, we compared the transcriptomes of KCNH2-mut pigs and WT controls
2025-02-03 | GSE288082 | GEO
Project description:Modeling Preeclampsia using human induced pluripotent stem cells
| PRJNA669030 | ENA
Project description:Modeling Preeclampsia using human induced pluripotent stem cells [methylation]
| PRJNA669029 | ENA
Project description:Osteochondral Tissue Chip Derived from iPSCs: Modeling OA pathologies and Testing Drugs
| PRJNA589299 | ENA
Project description:Our goal is to identify high-confidence candidate genes associated with sub-threshold QT interval loci. We predicted enhancer-promoter targets using two different methods.
2014-10-10 | GSE53567 | GEO
Project description:Engineered human cardiac tissues have been utilized for various biomedical applications, including drug testing, disease modeling, and regenerative medicine. However, the applications of cardiac tissues derived from human pluripotent stem cells are often limited due to their immaturity and lack of functionality. Therefore, in this study, we established a perfusable culture system based on in vivo-like heart microenvironments to improve human cardiac tissue fabrication. The integrated culture platform of a microfluidic chip and a three-dimensional heart extracellular matrix enhanced human cardiac tissue development and their structural and functional maturation. These tissues were comprised of cardiovascular lineage cells, including cardiomyocytes and cardiac fibroblasts derived from human induced pluripotent stem cells, as well as vascular endothelial cells. The resultant macroscale human cardiac tissues exhibited improved efficacy in drug testing (small molecules with various levels of arrhythmia risk), disease modeling (long QT syndrome and cardiac fibrosis), and regenerative therapy (myocardial infarction treatment). Therefore, our culture system can serve as a highly effective tissue-engineering platform to provide human cardiac tissues for versatile biomedical applications.
2024-02-03 | PXD042077 | Pride
Project description:Peribacillus frigoritolerans QT-140 TE12474 genome sequencing
| PRJNA1115250 | ENA
Project description:Cardiovascular disease remains a significant global health concern, yet the cardiotoxic effects of environmental chemicals are largely unexplored. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-Cardiomyocytes) are well-established as valuable high-throughput cardiotoxicity testing model based on the analysis of various beating parameters; however, additional adverse effects that may not be directly related to ion channel activity are difficult to ascertain from traditional assays. Transcriptomic data may provide a more comprehensive assessment for additional molecular responses and serve as a basis for dose-response analysis. We hypothesized that transcriptomic data and functional phenotypic measurements in iPSC-Cardiomyocytes could be used to effectively screen for both hazard and risk associated with chemical exposures. To test this hypothesis, we performed concentration-response analysis of 464 chemicals from 12 diverse chemical classes. Functional effects (beat frequency, QT-prolongation, and asystole) and cytotoxicity were measured. In addition, whole transcriptome RNA-seq was used to investigate global gene expression profiles. Points of departure (PODs) were derived from both phenotypic endpoints and transcriptomic data. Margin of safety (MOS) for drugs and margin of exposure (MOE) for non-drug chemicals were calculated using PODs and the exposure estimates. The phenotypic assays revealed that a varying proportion (10% to 44%) of chemicals in each class had effects on iPSC-Cardiomyocytes; positive chronotrope was the most sensitive phenotype. Overall, 244 (53%) chemicals were active in at least one functional phenotype. As expected, drugs with known adverse effects on the heart were most active. Transcriptomic data showed 69 (15%) had significant effects on the biological pathways, the pathways that were significantly affected by some tested compounds were highly relevant to cardiomyocyte function. Specifically, the enriched pathways aligned well with key characteristics of known cardiovascular toxicants, with mitochondrial dysfunction being the most affected key characteristic. Using exposure and hazard (transcriptomic and phenotypic PODs from this study), we derived MOS and MOE and found that drugs tend to have lower MOS than MOE for the environmental chemicals. Thirteen and 10 drugs had MOS < 1 using phenotypic and transcriptomic data, respectively, suggesting that further investigation may be needed for these substances to test for potential cardiovascular risk. Overall, our findings demonstrate how the integrative use of in vitro transcriptomic data and phenotypic assays in iPSC-Cardiomyocytes not only offers a unique and complementary approach for hazard and risk prioritization, but also offers comprehensive mechanistic support for in vitro test results.
2024-07-23 | GSE262419 | GEO