Tcruzi drug resistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB22622 | ENA |
REPOSITORIES: ENA
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Project description:Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally-derived F2s, and identified a single QTL (LOD=31) on chromosome 6. A sulfotransferase was identified as the causative gene using RNAi knockdown and biochemical complementation assays and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide. mRNA profiles from adult worms resistant (HR, 3 replicates) and susceptible (LE, 2 replicates) to the oxamniquine drug were compared to identify differential expression in genes related to drug resistance
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Project description:Background
Development of drug resistance is often dynamic and requires time series experiments to understand these processes. The most abundant source of information regarding such progressive activity is tracking single cell gene expression data. Our understanding of the imminent role of phenotype switching in modifying therapeutic response has considerably increased.The analysis of single cell transcriptomic data along with machine learning models offers a constructive tool to describe dynamic cellular processes to elucidate cell-to-cell variability within the population after drug exposure. Here we studied how genomic and non-genomic basis for transcriptome differences can influence the developing drug resistance and clonal fitness.
Results: This study describes the scRNA-seq analysis of untreated, treated and drug holiday PDX transplants of TNBC exposed to platinum. This builds from the materials and findings of our paper by Salehi, Kabeer et al, Nature 2021 (PMID: 3416307), in which we established the measurement of fitness in this time series. In the new work, we have mapped single cell transcription in conjunction, allowing a dissection of copy number driven (in-cis) clonal transcription and non-clonal, ie non-genomic transcription. We developed an experimental and computational platform consisting of four major steps: (1) timeseries sampling of scRNA-seq 126,556 TNBC PDX cells >2.5 years; (2) clustering the tumor cells into groups reflecting their drug sensitivity, resistance and other characteristics; (3) performing trajectory inference to identify lineages of transitional processes along with drug and tumor progression; (4) estimating the longitudinal gene expression of each lineage; and identifying significant genes between-lineage differential expression modules. Interestingly, we identified a small group of genes (18.9%) that display a new cell state that is not towards the untreated (Un-Rx) nor towards treated Rx which are distant from untreated cell states. The pathway results are shared between two different quantitative measurements of clone-aware differential expression and pseudotime analysis.
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Project description:Analysis of the mechanism of drug resistance regulated by Twist 1 at gene expression level. The hypothesis tested in the present study was that Twist 1 regulated the expression of drug resistance related genes. Results provide important information of the response of drug resistance related genes to Twist 1, either up- or down-regulated.
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