Inhibitor of prolyl-tRNA synthetase (PRS) to reduce tubulointerstitial nephritis
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ABSTRACT:
PROVIDER: PRJNA882069 | ENA |
REPOSITORIES: ENA
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Project description:Glutamyl-prolyl-transfer RNA synthetase (EPRS) is a class of enzymes that catalyze the attachment of 2 amino acids (i.e., glutamic acid and proline) to cognate transfer RNA for subsequent protein synthesis. Herein, we evaluated the effect of EPRS on the progression of tubulointerstitial nephritis using the mouse model with adenine-mixed diet. One single-cell RNA transcriptomic dataset was originated from wild-type mice, and other one was from heterozygous knockout mice, all of these were harvested at 2 weeks after adenine-mixed diet.
2022-09-24 | GSE213683 | GEO
Project description:Glutamyl-prolyl-tRNA synthetase (EPRS) is a unique bifunctional aminoacyl-tRNA synthetase which catalyzes the ATP-dependent aminoacylation of glutamyl and prolyl residues to cognate tRNAs, constituting fundamental building blocks in protein synthesis. Genomic data suggest that EPRS promotes disease progression and is associated with poor prognosis in multiple myeloma (MM), while downregulation of EPRS triggers MM cell apoptosis implying an amino acid starvation response as a central mechanism. We developed a novel ATP competitive inhibitor, NCP26, targeting the prolyl-tRNA synthetase (PRS) component. The inhibitor demonstrates significant anti-tumor activity against human MM cell lines, regardless of their sensitivity to other therapeutic agents, against patient MM cells and is active in vivo using a MM xenograft mouse model. In contrast to the proline competitive PRS inhibitor halofuginone, NCP26 effects are not altered by exogenous proline levels. NCP26 treatment induces G0/G1 cell cycle arrest followed by apoptotic MM cell death, evidenced by depletion of mitochondrial membrane potential as well as caspase and PARP cleavage. Using combined transcriptomic and proteomic approaches we demonstrate a complex phenotypic response involving multiple pathways in protein quality control which center around the ribosome as integrating hub. Furthermore, we identified multiple proline rich motif containing protein targets of NCP26 as downstream effectors. These include myeloma survival factors such as syndecan 1 (SDC1, CD138), or basic helix-loop-helix transcription factors such as MYC, and transcription factor 3 (TCF3) suggesting that acute blockade of prolyl- aminoacylation evokes a complex pro-apoptotic response beyond the canonical amino acid starvation and integrated stress response. Taken together, our pre-clinical studies validate EPRS as a possible therapeutic target and provide the framework for evaluation of PRS inhibitors in a clinical setting.
2022-09-08 | GSE186445 | GEO
Project description:Glutamyl-prolyl-tRNA synthetase (EPRS) is a unique bifunctional aminoacyl-tRNA synthetase which catalyzes the ATP-dependent aminoacylation of glutamyl and prolyl residues to cognate tRNAs, constituting fundamental building blocks in protein synthesis. Genomic data suggest that EPRS promotes disease progression and is associated with poor prognosis in multiple myeloma (MM), while downregulation of EPRS triggers MM cell apoptosis implying an amino acid starvation response as a central mechanism. We developed a novel ATP competitive inhibitor, NCP26, targeting the prolyl-tRNA synthetase (PRS) component. The inhibitor demonstrates significant anti-tumor activity against human MM cell lines, regardless of their sensitivity to other therapeutic agents, against patient MM cells and is active in vivo using a MM xenograft mouse model. In contrast to the proline competitive PRS inhibitor halofuginone, NCP26 effects are not altered by exogenous proline levels. NCP26 treatment induces G0/G1 cell cycle arrest followed by apoptotic MM cell death, evidenced by depletion of mitochondrial membrane potential as well as caspase and PARP cleavage. Using combined transcriptomic and proteomic approaches we demonstrate a complex phenotypic response involving multiple pathways in protein quality control which center around the ribosome as integrating hub. Furthermore, we identified multiple proline rich motif containing protein targets of NCP26 as downstream effectors. These include myeloma survival factors such as syndecan 1 (SDC1, CD138), or basic helix-loop-helix transcription factors such as MYC, and transcription factor 3 (TCF3) suggesting that acute blockade of prolyl- aminoacylation evokes a complex pro-apoptotic response beyond the canonical amino acid starvation and integrated stress response. Taken together, our pre-clinical studies validate EPRS as a possible therapeutic target and provide the framework for evaluation of PRS inhibitors in a clinical setting.
2022-09-08 | GSE186447 | GEO
Project description:Nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these models. In this study we used an unbiased transcriptional network approach to define similarities and differences between three lupus models and human LN. Affymetrix-based expression profiles were analyzed using Genomatix Bibliosphere software and transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE). The 20 network hubs (nodes) shared between all three models and human LN reflect key pathologic processes, namely immune cell infiltration/activation, macrophage/dendritic cell activation, endothelial cell activation/injury and tissue remodeling/fibrosis. Each model also shares unique features with human LN. Pathway analysis of the TALE nodes highlighted macrophage/DC activation as a cross-species shared feature. To distinguish which genes and activation pathways might derive from mononuclear phagocytes in the human kidneys the gene expression profile of isolated NZB/W renal mononuclear cells was compared with human LN kidney profiles. Network analysis of the shared signature highlighted NFkappaB1 and PPARgamma as major hubs in the tubulointerstitial and glomerular networks respectively. Key nodes in the renal macrophage inflammatory response form the basis for further mechanistic and therapeutic studies. We used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with lupus nephritis (LN) RNA from glomeruli and tubulointerstitial compartments was extracted and processed for hybridization on Affymetrix microarrays.
2012-06-27 | E-GEOD-32591 | biostudies-arrayexpress
Project description:Pharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), PTC-LRP2 +/+ and -/- littermates in an LDL receptor -/- background were generated and fed a Western diet to determine effects of PTC-derived megalin on atherosclerosis. PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 -/- mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. By contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney. Overall, PTC-specific megalin deletion leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.
2024-07-04 | GSE268879 | GEO
Project description:AKT signaling pathway plays critical roles in the resolution of inflammation. However, the underlying mechanisms of anti-inflammatory regulation and signal coordination remain unclear. Here, we report that anti-inflammatory AKT signaling is coordinated by glutamyl-prolyl-tRNA synthetase 1 (EPRS1). Upon inflammatory activation, AKT specifically phosphorylated Ser999 of EPRS1 in the cytoplasmic multi-tRNA synthetase complex, inducing release of EPRS1. The EPRS1 compartmentalized AKT to early endosomes via selective binding to the endosomal membrane lipid phosphatidylinositol 3-phosphate and assembled an AKT signaling complex specific for anti-inflammatory activity. These events promoted AKT activation-mediated GSK3β phosphorylation, which increased anti-inflammatory cytokine production. EPRS1-deficient macrophages could not assemble the early endosomal complex and consequently exacerbated inflammation, decreasing the survival of EPRS1-deficient mice undergoing septic shock and ulcerative colitis. Collectively, our findings show that the housekeeping protein EPRS1 acts as a mediator of inflammatory homeostasis by coordinating compartment-specific AKT signaling
2022-10-12 | PXD036072 | Pride
Project description:Renal Proximal Tubule Cell-specific Megalin Deletion Induces Tubulointerstitial Nephritis in Mice Fed Western Diet
| PRJNA1119377 | ENA
Project description:Expression data from human with hypertensive nephropathy (HT) We used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with HT RNA from glomeruli and tubulointerstitial compartments was extracted and processed for hybridization on Affymetrix microarrays.
2012-12-10 | E-GEOD-37455 | biostudies-arrayexpress
Project description:We profiled manually microdissected tubulointerstitial tissue from 43 IgA nephropathy, 3 diabetes mellitus nephropathy, 3 focal segmental glomerulosclerosis, 3 lupus nephritis, 4 membranous nephropathy, and 9 minimal change disease biopsy cores and 22 nephrectomy controls by RNA sequencing. The 3 outliers which were not included in our main analysis were also uploaded in this database.
2022-05-02 | GSE175759 | GEO
Project description:Targeting prolyl-tRNA synthetase via a series of ATP-mimetics to accelerate drug discovery against toxoplasmosis
| PRJNA896924 | ENA