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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: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: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: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
Project description:Human induced pluripotent stem cell-derived kidney organoids have potential for disease modelling and regenerative medicine purposes. However, they lack a functional vasculature and remain immature in in vitro culture. Here, we transplanted kidney organoids at day 7+12 of differentiation in the coelomic cavity of chicken embryos and then compared them to their respective untransplanted controls at d7+13 and d7+20 using scRNAseq and imaging modalities. We demonstrate vascularization and enhanced maturation of transplanted kidney organoids.
2022-08-05 | E-MTAB-11429 | biostudies-arrayexpress
Project description:An organoids-on-a-chip model of human ARPKD
| PRJNA786570 | ENA
Project description:Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3, COL4A4 or COL4A5 gene mutations and characterized by abnormalities of glomerular basement membranes (GBMs). Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents. Hampering drug discovery is the absence of effective in vitro methods for testing the restoration of normal GBMs. Here, we aimed to develop kidney organoid models from AS patient iPSCs for this purpose. We established iPSC-derived collagen α5(IV)-expressing kidney organoids and confirmed that kidney organoids from COL4A5 mutation-corrected iPSCs restore collagen α5(IV) protein expression. Importantly, our model recapitulates the differences in collagen composition between iPSC-derived kidney organoids from mild and severe AS cases. Furthermore, we demonstrate that a chemical chaperone, 4-phenyl butyric acid, has the potential to correct GBM abnormalities in kidney organoids showing mild AS phenotypes. This iPSC-derived kidney organoid model will contribute to drug discovery for AS.
2023-07-06 | GSE236314 | GEO
Project description:To investigate the impact of various NPHS2 homozygous point mutations on podocyte biology in induced pluripotent stem cell (iPSC)-derived human kidney organoids, an iPSC allelic series was generated from a control fibroblast line and two iPSC lines were derived from patient blood samples (one homozygous R168H and one unaffected relative) iPSCs were differentiated into kidney organoids, organoids glomeruli were harvested and we performed gene expression profiling using data obtained from RNA-seq of 3 sets of 4 organoids for each genotype at D7+14 of our differentiation protocol (Takasato et al, Nature 2016)
2022-09-07 | GSE205647 | GEO
Project description:Purpose: A proof of concept study examining the disease modelling capabilities of patient iPSC derived kidney organoids. Methods: A proband was diagnosed by genome sequencing with compound heterozygous IFT140 mutations. A one-step reprogramming/gene-editing protocol of proband fibroblasts was used to derive both uncorrected patient and isogenic gene-corrected induced pluripotent stem cells (iPSC) which were differentiated to kidney organoids. Organoids were examined by immunofluorescence. Additionally, epithelial cells magnetically sorted from whole kidney organoids underwent transcriptional profiling and spheroid culture. Results: Differential expression analysis of organoid epithelial cell fractions demonstrated apicobasal polarity, cell-cell junction and dynein motor assembly downregulation in patient organoids. Defective ciliary morphology and spheroid culture were rescued in gene corrected organoids. Conclusions: This study validates patient iPSC-derived kidney organoids as a novel, faithful and patient-specific model to further the study of inherited renal disease in regenerated, human, in vitro tissue.
2018-04-26 | GSE107230 | GEO
Project description:The individualized treatment of tumors has always been an urgent problem in clinical practice. Organoids-on-a-chip can reflect the heterogeneity of tumors and is a good model for in vitro anticancer drug screening. In this study, surgical specimens of patients with advanced colorectal cancer will be collected for organoid culture and organoids-on-a- chip. Use organoids-on-a-chip to screen tumor chemotherapy drugs, compare the results of patients’ actual medication regimens, and study the guiding role of organoids in the formulation of precise tumor treatment plans. The investigators will compare the response of organoids to drugs in vitro with the patient’s response to actual chemotherapy and targeted drugs and explore the feasibility and accuracy of organoids-on-a-chip based drug screening for advanced colorectal cancer. The project will establish a screening platform for chemotherapeutic drugs and targeted drugs based on colorectal cancer organoids to quickly and accurately formulate personalized treatment plans for clinical patients.
| 2385953 | ecrin-mdr-crc