FM2001-TSA
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR475357_1.fastq.gz | Fastqsanger.gz | |||
| ERR475357_2.fastq.gz | Fastqsanger.gz |
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Project description:Congenital hepatic fibrosis in the Franches-Montagnes horse is associated with the polycystic kidney and hepatic disease 1 (PKHD1) gene
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Project description:Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by mutations in the gene PKHD1. ARPKD presents with considerably clinical variability which is linked to the type of PKHD1 mutation but not position. Animal models of Polycystic Kidney Disease (PKD) suggest there is a complex genetic landscape with genetic modifiers as a potential cause of disease variability. Transcriptomic analysis identified a considerable number of genes linked to cellular metabolism and development. Amongst these genes were those linked to WNT signalling. Two individuals in this cohort had the same mutations in PKHD1 but different rates of kidney disease progression. Amongst the transcriptomic differences of these two individuals were differences in the expression changes of WNT genes.
2024-09-06 | GSE242476 | GEO
Project description:Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal cystic disease mainly caused by PKHD1. However, its genetic cause, pathological features, and mechanism remained unsolved. Our findings may provide new insight on the pathophysiology of the polycystic kidney due to PKHD1 deficiency, and the PKHD1 mosaicism needs to be taken close attention in genetic testing of ARPKD.
2021-08-20 | PXD028042 |
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of ESRD. Affected individuals inherit a defective copy of either the PKD1 or PKD2 gene, encoding the proteins polycystin?1 (PC1) or polycystin?2 (PC2) respectively. PC1 and PC2 are secreted on urinary exosome?like vesicles (ELVs) (100nm diameter vesicles), where PC1 is present in a cleaved form and may be complexed with PC2. Label free quantitative proteomic studies of urine ELVs in an initial discovery cohort (13 PKD1 and 18 Normals), revealed that of 2008 ELV proteins, nine (0.32%) showed a statistically significant difference between PKD1 and normals at a p<0.025. PC1 was reduced to 54% of the normal level (p<0.02) and PC2 reduced to 53% (p<0.001). TMEM2, a protein with homology to fibrocystin, the product of the polycystic hepatic and kidney disease (PKHD1) gene, is increased 2.1 fold (p<0.025). The PC1/TMEM2 ratio correlated inversely with height adjusted total kidney volume (HtTKV) in the discovery cohort and the ratio of PC1/TMEM2 or PC2/TMEM2 could be used to distinguish PKD1 from normals in a confirmation cohort. In summary, this study suggests that a test based on the urine exosomal PC1/TMEM2 or PC2/TMEM2 ratio may have utility in the diagnosis and perhaps monitoring of PKD1.
2014-12-02 | PXD001075 | Pride
Project description:(1) Background: Polycystic liver disease (PLD) is a heterogeneous group of congenital disorders characterized by bile duct dilatation and cyst development derived from cholangiocytes. Nevertheless, the cystogenesis mechanism is currently unknown and the PLD treatment is limited to liver transplantation. Novel and efficient therapeutic approaches are th6us needed. In this context, the present work has a principal aim to find novel molecular pathways, as well as new therapeutic targets, involved in the hepatic cystogenesis process. (2) Methods: Quantitative proteomics based on SWATH–MS technology were performed comparing hepatic proteomes of Wild Type and mutant/polycystic livers in a polycystic kidney disease (PKD) murine model (Pkd1cond/cond;Tam-Cre−/+). (3) Results: We identified several proteins altered in abundance, with twofold cut-off up-regulation or down-regulation and an adjusted p-value significantly related to hepatic cystogenesis. Then, we performed enrichment and a protein–protein analysis identifying a cluster focused on hepatic fibrinogens. Finally, we validated a selection of targets by RT-qPCR, Western blotting and immunohistochemistry, finding a high correlation with quantitative proteomics data and validating the fibrinogen complex. (4) Conclusions: This work identified a novel molecular pathway in cystic liver disease, highlighting the fibrinogen complex as a possible new therapeutic target for PLD.
2022-04-04 | PXD031253 | Pride
Project description:Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene in both humans and the orthologous PCK rat model. Although ARPKD results solely from PKHD1 mutations, the disease onset and severity are highly variable, indicating that other unknown genetic risk factor(s) modify ARPKD-associated phenotypes. To identify genetic modifiers of ARPKD severity, we created two genetically distinct Pkhd1 congenic rat strains on the Fawn-Hooded Hypertensive (FHH) and the Dahl S (SS) rat backgrounds (denoted FHH.Pkhd1 and SS.Pkhd1, respectively) that harbor the PCK-derived Pkhd1 allele. The FHH.Pkhd1 and SS.Pkhd1 strains had lower renal cyst formation at 30 days-of-age (5±2% and 8±2% cystic, respectively; P<0.001) compared to the PCK kidneys (26±4% cystic), which coincided with significantly reduced kidney weights in the FHH.Pkhd1 and SS.Pkhd1. Liver cyst formation and liver weight did not differ between PCK, FHH.Pkhd1, and SS.Pkhd1. These data indicated that the PCK genome harbors genetic modifier(s) of ARPKD severity that are not present in the FHH and SS genomes. Using high density SNP array genotyping and microarray expression analysis, we identified 50 potential modifiers of ARPKD severity in the PCK rat. Of these candidates, a damaging nonsynonymous variant in Nphp4 stood out as the most likely candidate based on variant segregation, protein modeling, network analysis, and gene ontology. Nphp4 is widely associated with the autosomal recessive cilliopathy and nephronopthisis, but had not been previously implicated in the molecular or cellular pathophysiology of ARPKD. Collectively, these data provide genetic evidence of disease modifier(s) in the PCK model of ARPKD and prioritized multiple candidates, including NPHP4, for further investigation in ARPKD pathogenesis. In this study, we used microarray to analyze transcript expression in the kidneys of 30 day old SD (n=4), PCK (n=4), FHH (n=4), FHH.Pkhd1 (n=4), SS (n=4), and SS.Pkhd1 (n=4). Samples were pooled and the pooled samples were run in triplicate. The 30 day timepoint was chosen because the differences in renal cyst formation between PCK, FHH.Pkhd1, and SS.Pkhd1 were greatest at this timepoint. To account for genetic strain differences that do not contribute to ARPKD severity, gene expression of each cystic rat strain was compared to its parental strain.
2015-06-06 | E-GEOD-58229 | biostudies-arrayexpress
Project description:During development, distinct progenitors contribute to the nephrons versus the ureteric epithelium of the kidney. Indeed, previous pluripotent stem cell-derived models of kidney tissue either contain nephrons or pattern specifically to the ureteric epithelium. By reanalysing the transcriptional distinction between distal nephron and ureteric epithelium in human fetal kidney, we show here that while existing nephron-containing kidney organoids contain distal nephron epithelium and no ureteric epithelium, this distal nephron segment alone displays significant in vitro plasticity and can adopt a ureteric epithelial tip identity when isolated and cultured in defined conditions. “Induced” ureteric epithelium cultures can be cryopreserved, serially passaged without loss of identity and transitioned towards a collecting duct fate. Indeed, cultures harbouring loss-of-function mutations in PKHD1 recapitulate the cystic phenotype associated with autosomal recessive polycystic kidney disease.
2021-01-15 | GSE161255 | GEO
Project description:Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene in both humans and the orthologous PCK rat model. Although ARPKD results solely from PKHD1 mutations, the disease onset and severity are highly variable, indicating that other unknown genetic risk factor(s) modify ARPKD-associated phenotypes. To identify genetic modifiers of ARPKD severity, we created two genetically distinct Pkhd1 congenic rat strains on the Fawn-Hooded Hypertensive (FHH) and the Dahl S (SS) rat backgrounds (denoted FHH.Pkhd1 and SS.Pkhd1, respectively) that harbor the PCK-derived Pkhd1 allele. The FHH.Pkhd1 and SS.Pkhd1 strains had lower renal cyst formation at 30 days-of-age (5±2% and 8±2% cystic, respectively; P<0.001) compared to the PCK kidneys (26±4% cystic), which coincided with significantly reduced kidney weights in the FHH.Pkhd1 and SS.Pkhd1. Liver cyst formation and liver weight did not differ between PCK, FHH.Pkhd1, and SS.Pkhd1. These data indicated that the PCK genome harbors genetic modifier(s) of ARPKD severity that are not present in the FHH and SS genomes. Using high density SNP array genotyping and microarray expression analysis, we identified 50 potential modifiers of ARPKD severity in the PCK rat. Of these candidates, a damaging nonsynonymous variant in Nphp4 stood out as the most likely candidate based on variant segregation, protein modeling, network analysis, and gene ontology. Nphp4 is widely associated with the autosomal recessive cilliopathy and nephronopthisis, but had not been previously implicated in the molecular or cellular pathophysiology of ARPKD. Collectively, these data provide genetic evidence of disease modifier(s) in the PCK model of ARPKD and prioritized multiple candidates, including NPHP4, for further investigation in ARPKD pathogenesis.
2015-06-06 | GSE58229 | GEO
Project description:Liver fibrosis usually involve different cell types interaction. Despite its devastating consequences, there are no treatments for liver fibrosis. Genome engineering and a human hepatic organoid system was used to produce the first naïve in vitro model including several crucial components contributed for liver fibrosis. Hepatic organoids engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD) developed abnormal bile ducts and hepatic fibrosis in only 21 days, which are the key features of ARPKD liver pathology. Singel cell level analysis indicated that the ARPKD mutation induced bile duct proliferation through several critial pathways, and appear to be actively involved in collagen fiber generation. Therefore, abnormal cholangiocytes promotes the expansion its counterpart , which collagen-producing myofibroblasts with a markedly increased level of PDGFRB protein expression and evidence of an activated STAT3 signalling pathway.
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Project description:Polycystic Kidney Disease (PKD) is a devastating inherited kidney disease that is a major cause of kidney failure. Large fluid-filled cysts develop in the kidney and continually expand over time, damaging the surrounding tissue until renal replacement therapy is required. Because the development of cysts is the major feature of this disease, researchers have long sought to determine the composition of cystic fluid. To the best of our knowledge, no one has previously published the ion concentrations of cystic fluid from any PKD rodent models. The overall goal of this study was to characterize the cyst fluid composition of a rat model of ARPKD, the PCK rat. This model developed spontaneously from the Charles River Japan cesarean derived Sprague Dawley (Crj:CD/SD) strain and features a mutation in Pkhd1, the ortholog to the causative ARPKD gene in humans. In addition to analyzing cystic fluid, we complemented our metabolomics approach with transcriptomic analysis of male and female PCK rat kidney cortex tissue.
2024-03-30 | GSE261500 | GEO