Targeting the ADPKD methylome using nanoparticle-mediated combination therapy
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ABSTRACT:
PROVIDER: PRJNA834131 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19039246_1.fastq.gz | Fastqsanger.gz | |||
| SRR19039246_2.fastq.gz | Fastqsanger.gz | |||
| SRR19039247_1.fastq.gz | Fastqsanger.gz | |||
| SRR19039247_2.fastq.gz | Fastqsanger.gz | |||
| SRR19039248_1.fastq.gz | Fastqsanger.gz |
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Project description:DNA methylation aberrancies are found in autosomal dominant polycystic kidney disease (ADPKD) which suggest the methylome to be a promising therapeutic target. However, the impact of combining DNA methylation inhibitors (DNMTi) and ADPKD drugs in treating ADPKD and on disease-associated methylation patterns has not been fully explored. To test this, ADPKD drugs, metformin and tolvaptan (MT), were delivered in combination with DNMTi 5-aza-2’-deoxycytidine (Aza) to 2D or 3D cystic Pkd1 heterozygous renal epithelial cells (PKD1-Het cells) as free drugs or within nanoparticles to enable direct delivery for future in vivo applications. We found Aza synergizes with MT to reduce cell viability and cystic growth. Reduced representation bisulfite sequencing (RRBS) was performed across 4 groups: PBS, Free-Aza (Aza), Free-Aza+MT (F-MTAza), and Nanoparticle-Aza+MT (NP-MTAza). Global methylation patterns showed that while Aza alone induces a unimodal intermediate methylation landscape, Aza+MT recovers the bimodality reminiscent of somatic methylomes. Importantly, site-specific methylation changes associated with F-MTAza and NP-MTAza were largely conserved including hypomethylation at ADPKD-associated genes. Notably, we report hypomethylation of cancer-associated genes implicated in ADPKD pathogenesis as well as new target genes that may provide additional therapeutic effects. Overall, this study motivates future work to further elucidate the regulatory mechanisms of observed drug synergy and apply these combination therapies in vivo.
2023-05-10 | GSE202065 | GEO
Project description:We have previously described global hypomethylation and site-specific DNA methylation changes which are associated with disease-state renal tissue in Autosomal Dominant Polycystic Kidney Disease (ADPKD). However, to-date there are no available data on the pattern of DNA methylation across an ADPKD kidney. Here we describe the methylome of eight individual cysts from a single ADPKD patient and peform an intra-individual analysis to identify regions of DNA methylation variability.
2020-01-14 | GSE142664 | GEO
Project description:We performed a proteomic analysis of kidneys samples from mice with ADPKD and 3az- treated mice with ADPKD to explore the mechanisms of 3az treatment in ADPKD. Over 5000 proteins were obtained in kidney tissues from ADPKD group and drug administration group. Among them, 112 and 135 proteins were found up- and down-regulation between two groups, respectively. Gene Ontology (GO) analysis of these dysregulated proteins preliminarily revealed that the proteins regulated by 3az were mainly enriched in many biological processes. In particular, microtubule-based processes, microtubule cytoskeleton formation and mitotic cell cycle changed most significantly and were enriched in a great many of dysregulated proteins following 3az treatment in ADPKD mice. GSEA enrichment analysis demonstrated that compound 3az can down-regulate the proliferation ability of kidney in ADPKD mice. Microtubule-based processes and microtubule cytoskeleton formation have been reported to be associated with retard of cell proliferation and renal cyst expansion.
2024-02-20 | PXD049792 | Pride
Project description:To investigate altered expression patterns of key miRNAs in end-stage ADPKD kidneys, a miRNA microarray analysis was performed using non-ADPKD and ADPKD kidney tissue samples. As a result, total 19 miRNAs were significantly changed in the ADPKD samples compared with non-ADPKD samples. Among these miRNAs, the expression level of the miR-192 family including miR-192 and miR-194 were significantly downregulated in ADPKD.
2019-07-30 | GSE100812 | GEO
Project description:We report scRNA-seq data showing the effect of palbociclib treatment on medulloblastomas that form in Smo-mutant mice. We generate tumor-bearing mice by breeding hGFAP-Cre and SmoM2 mouse lines to prodce tumor-prone progeny heterozygous for both transgenes (G-Smo mice). We compare tumors from untreated G-Smo mice to tumors from G-Smo ice treated with nanoparticle--delievered palbociclib, using Drop-seq-based scRNA-seq.
2021-11-16 | GSE188672 | GEO
Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors. The gene expression profiles of vascular endothelia and smooth muscle cells derived from ADPKD-iPSCs were analyzed. Seven ADPKD-iPSC derived ECs, and seven ADPKD-iPSC derived SMCs were analyzed.
2016-08-04 | E-GEOD-74452 | biostudies-arrayexpress
Project description:From serum samples of non-dialyzed and dialyzed patients with ADPKD and healthy control total RNA was isolated and miRNA expression was evaluated. Circulating microRNAs (miRNA) are important intercellular communication compounds. We investigated the influence of ADPKD (autosomal dominant polycystic kidney disease) and hemodialysis on the profile of serum miRNAs. We found 37 significant circulating miRNA that differ between ADPKD patients (dialyzed and non-dialyzed) and healthy controls. Bioinformatic analysis revealed strongest connections between those miRNAs and KEGG pathway: MicroRNAs in cancer. We selected 3 miRNAs with highest and 3 with lowest fold change in comparison of dialyzed and non-dialyzed patients and compared their expression in paired pre-/post-dialysis samples. All up-regulated miRNAs (miR-532-3p, miR-320b, miR-144-5p) were not significantly altered by hemodialysis. From down-regulated miRNAs miR-27a-3p was shown to be significantly lower after dialysis in both total and exosomal fraction. MiR-20a-5p was down-regulated after dialysis only in the exosomal fraction whereas miR-16-5p was unaltered by hemodialysis. MiR-16-5p was selected as the best circulating biomarker of ADPKD with miR-22-3p, let-7i-5p and miR-24-3p as following best ones. Circulating representatives of miR-17 family (new drug target of ADPKD (Hajarnis et al. 2017)) sharing the same seed region (miR-20a-5p, miR-93-5p and miR-106a-5p) showed significantly lowered expressed in sera of dialyzed patients vs non-dialyzed ones and their exosomal fraction dropped after hemodialysis. We concluded that serum miRNA among ADPKD patients differ substantially depending on the stage of CKD. These alterations show possible links with cancer. The exosomal fraction of miRNA was more affected by dialysis than total fraction of miRNAs suggesting their dynamically changing functional role.
2018-06-30 | GSE101811 | GEO
Project description:Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib
| PRJNA779922 | ENA
Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors. The gene expression profiles of vascular endothelia and smooth muscle cells derived from control- and ADPKD-iPSCs were analyzed. Seven control-iPSC derived endothelial cells (ECs), seven ADPKD-iPSC derived ECs, ten control-iPSC derived vascular smooth muscle cells (SMCs), and seven ADPKD-iPSC derived SMCs were analyzed.
2016-08-04 | E-GEOD-74451 | biostudies-arrayexpress
Project description:Mechanism of activation of porcine dendritic cells by an alpha-D-glucan nanoparticle adjuvant and nanoparticle/poly(I:C) combination adjuvant.
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