Summary of Study ST003113

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001933. The data can be accessed directly via it's Project DOI: 10.21228/M8VM8W This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

Perform statistical analysis  |  Show all samples  |  Show named metabolites  |  Download named metabolite data  
Download mwTab file (text)   |  Download mwTab file(JSON)   |  Download data files (Contains raw data)
Study IDST003113
Study TitleInhibition of Asparagine Synthetase Effectively Retards Polycystic Kidney Disease Progression, investigated with targeted tracing metabolomics analysis in MEF cells using 15N2-glutamine.
Study SummaryPolycystic Kidney Disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD. Of interest, in these tracing studies we could confirm that the pyrimidine biosynthesis pathway is increased and rescued by silencing of Asns.
Institute
San Raffaele University
Last NameStefanoni
First NameDavide
AddressVia Olgettina 58, Milan, Milan, 20132, Italy
Emailstefanoni.davide@hsr.it
Phone+393337686005
Submit Date2024-02-28
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2024-04-30
Release Version1
Davide Stefanoni Davide Stefanoni
https://dx.doi.org/10.21228/M8VM8W
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Sample source Treatment
SA3373182DG_1Brain 2DG
SA3373192DG_5Brain 2DG
SA3373202DG_4Brain 2DG
SA3373212DG_2Brain 2DG
SA3373222DG_3Brain 2DG
SA337323Saline_5Brain Saline
SA337324Saline_4Brain Saline
SA337325Saline_1Brain Saline
SA337326Saline_2Brain Saline
SA337327Saline_3Brain Saline
SA33734037MEF cells Labeled_siASNS_11_1
SA33734138MEF cells Labeled_siASNS_11_2
SA33734239MEF cells Labeled_siASNS_11_3
SA33734340MEF cells Labeled_siASNS_11_4
SA33734441MEF cells Labeled_siASNS_11_5
SA33734542MEF cells Labeled_siASNS_11_6
SA33734643MEF cells Labeled_siASNS_14_1
SA33734744MEF cells Labeled_siASNS_14_2
SA33734845MEF cells Labeled_siASNS_14_3
SA33734946MEF cells Labeled_siASNS_14_4
SA33735047MEF cells Labeled_siASNS_14_5
SA33735148MEF cells Labeled_siASNS_14_6
SA33732813MEF cells Labeled_Untreated_11_1
SA33732914MEF cells Labeled_Untreated_11_2
SA33733015MEF cells Labeled_Untreated_11_3
SA33733116MEF cells Labeled_Untreated_11_4
SA33733217MEF cells Labeled_Untreated_11_5
SA33733318MEF cells Labeled_Untreated_11_6
SA33733419MEF cells Labeled_Untreated_14_1
SA33733520MEF cells Labeled_Untreated_14_2
SA33733621MEF cells Labeled_Untreated_14_3
SA33733722MEF cells Labeled_Untreated_14_4
SA33733823MEF cells Labeled_Untreated_14_5
SA33733924MEF cells Labeled_Untreated_14_6
SA3373521MEF cells Unlabeled_Untreated_11_1
SA3373532MEF cells Unlabeled_Untreated_11_2
SA3373543MEF cells Unlabeled_Untreated_11_3
SA3373554MEF cells Unlabeled_Untreated_11_4
SA3373565MEF cells Unlabeled_Untreated_11_5
SA3373576MEF cells Unlabeled_Untreated_11_6
SA3373587MEF cells Unlabeled_Untreated_14_1
SA3373598MEF cells Unlabeled_Untreated_14_2
SA3373609MEF cells Unlabeled_Untreated_14_3
SA33736110MEF cells Unlabeled_Untreated_14_4
SA33736211MEF cells Unlabeled_Untreated_14_5
SA33736312MEF cells Unlabeled_Untreated_14_6
Showing results 1 to 46 of 46
  logo