{
"METABOLOMICS WORKBENCH":{"STUDY_ID":"ST003113","ANALYSIS_ID":"AN005100","VERSION":"1","CREATED_ON":"February 29, 2024, 3:20 pm"},

"PROJECT":{"PROJECT_TITLE":"Inhibition of Asparagine Synthetase Effectively Retards Polycystic Kidney Disease Progression.","PROJECT_SUMMARY":"Polycystic 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 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_NAME":"Stefanoni","FIRST_NAME":"Davide","ADDRESS":"Via Olgettina 58, Milan, Milan, 20132, Italy","EMAIL":"stefanoni.davide@hsr.it","PHONE":"+393337686005"},

"STUDY":{"STUDY_TITLE":"Inhibition of Asparagine Synthetase Effectively Retards Polycystic Kidney Disease Progression, investigated with targeted tracing metabolomics analysis in MEF cells using 15N2-glutamine.","STUDY_SUMMARY":"Polycystic 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_NAME":"Stefanoni","FIRST_NAME":"Davide","ADDRESS":"Via Olgettina 58, Milan, Milan, 20132, Italy","EMAIL":"stefanoni.davide@hsr.it","PHONE":"+393337686005"},

"SUBJECT":{"SUBJECT_TYPE":"Mammal","SUBJECT_SPECIES":"Mus musculus","TAXONOMY_ID":"10090"},
"SUBJECT_SAMPLE_FACTORS":[
{
"Subject ID":"-",
"Sample ID":"1",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_11_1"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-1"}
},
{
"Subject ID":"-",
"Sample ID":"2",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_11_2"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-2"}
},
{
"Subject ID":"-",
"Sample ID":"3",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_11_3"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-3"}
},
{
"Subject ID":"-",
"Sample ID":"4",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_11_4"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-4"}
},
{
"Subject ID":"-",
"Sample ID":"5",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_11_5"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-5"}
},
{
"Subject ID":"-",
"Sample ID":"6",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_11_6"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-6"}
},
{
"Subject ID":"-",
"Sample ID":"7",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_14_1"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-7"}
},
{
"Subject ID":"-",
"Sample ID":"8",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_14_2"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-8"}
},
{
"Subject ID":"-",
"Sample ID":"9",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_14_3"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-9"}
},
{
"Subject ID":"-",
"Sample ID":"10",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_14_4"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-10"}
},
{
"Subject ID":"-",
"Sample ID":"11",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_14_5"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-11"}
},
{
"Subject ID":"-",
"Sample ID":"12",
"Factors":{"Sample source":"MEF cells","Factor":"Unlabeled_Untreated_14_6"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-12"}
},
{
"Subject ID":"-",
"Sample ID":"13",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_11_1"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-13"}
},
{
"Subject ID":"-",
"Sample ID":"14",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_11_2"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-14"}
},
{
"Subject ID":"-",
"Sample ID":"15",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_11_3"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-15"}
},
{
"Subject ID":"-",
"Sample ID":"16",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_11_4"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-16"}
},
{
"Subject ID":"-",
"Sample ID":"17",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_11_5"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-17"}
},
{
"Subject ID":"-",
"Sample ID":"18",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_11_6"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-18"}
},
{
"Subject ID":"-",
"Sample ID":"19",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_14_1"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-19"}
},
{
"Subject ID":"-",
"Sample ID":"20",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_14_2"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-20"}
},
{
"Subject ID":"-",
"Sample ID":"21",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_14_3"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-21"}
},
{
"Subject ID":"-",
"Sample ID":"22",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_14_4"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-22"}
},
{
"Subject ID":"-",
"Sample ID":"23",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_14_5"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-23"}
},
{
"Subject ID":"-",
"Sample ID":"24",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_Untreated_14_6"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-24"}
},
{
"Subject ID":"-",
"Sample ID":"37",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_11_1"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-37"}
},
{
"Subject ID":"-",
"Sample ID":"38",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_11_2"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-38"}
},
{
"Subject ID":"-",
"Sample ID":"39",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_11_3"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-39"}
},
{
"Subject ID":"-",
"Sample ID":"40",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_11_4"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-40"}
},
{
"Subject ID":"-",
"Sample ID":"41",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_11_5"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-41"}
},
{
"Subject ID":"-",
"Sample ID":"42",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_11_6"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-42"}
},
{
"Subject ID":"-",
"Sample ID":"43",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_14_1"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-43"}
},
{
"Subject ID":"-",
"Sample ID":"44",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_14_2"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-44"}
},
{
"Subject ID":"-",
"Sample ID":"45",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_14_3"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-45"}
},
{
"Subject ID":"-",
"Sample ID":"46",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_14_4"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-46"}
},
{
"Subject ID":"-",
"Sample ID":"47",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_14_5"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-47"}
},
{
"Subject ID":"-",
"Sample ID":"48",
"Factors":{"Sample source":"MEF cells","Factor":"Labeled_siASNS_14_6"},
"Additional sample data":{"RAW_FILE_NAME(compound)":"CA24_06-48"}
}
],
"COLLECTION":{"COLLECTION_SUMMARY":"Immortalized Pkd1+/+ and Pkd1−/− MEFs were cultured in either culture media enriched with and without 15N2-glutamine. Following 24h were collected, pellet and instantly extracted with metabolomics lysis buffer.","SAMPLE_TYPE":"Cultured cells"},

"TREATMENT":{"TREATMENT_SUMMARY":"Immortalized Pkd1+/+ and Pkd1−/− MEFs were cultured in either culture media enriched or not with 15N2-glutamine."},

"SAMPLEPREP":{"SAMPLEPREP_SUMMARY":"MEF cells samples were extracted in a ratio of 1milion/1mL of ice cold extraction solution (methanol:acetonitrile:water 5:3:2 v/v/v). Suspensions were vortexed continuously for 30 min at 4°C. Insoluble material was removed by centrifugation at 18,000 g for 10 min at 4°C and supernatants were isolated for metabolomics analysis by UHPLC-MS."},

"CHROMATOGRAPHY":{"CHROMATOGRAPHY_SUMMARY":"5MM_POS_ESI","CHROMATOGRAPHY_TYPE":"Reversed phase","INSTRUMENT_NAME":"Thermo Vanquish","COLUMN_NAME":"Phenomenex Kinetex C18 (150 x 2.1mm,1.7um)","SOLVENT_A":"100% water; 0.1% formic acid","SOLVENT_B":"100% acetonitrile","FLOW_GRADIENT":"0-0.5 min 5% B, 0.5-1.1 min 5-95% B, 1.1-2.75 min hold at 95% B, 2.75-3 min 95-5% B, 3-5 min hold at 5% B.","FLOW_RATE":"0.450ml/min","COLUMN_TEMPERATURE":"45°C"},

"ANALYSIS":{"ANALYSIS_TYPE":"MS","LABORATORY_NAME":"Angelo D''Alessandro Lab"},

"MS":{"INSTRUMENT_NAME":"Thermo Q Exactive Orbitrap","INSTRUMENT_TYPE":"Orbitrap","MS_TYPE":"ESI","ION_MODE":"POSITIVE","MS_COMMENTS":"The Q Exactive was run independently in positive and negative ion mode, scanning using full MS from 125-1500 m/z at 70,000 resolution and top 10 data-dependent MS2 at 17,500 resolution. Electrospray ionization was achieved with 45 Arb sheath gas, 25 Arb auxiliary gas, and 4 kV spray voltage. Calibration was performed prior to the run using the PierceTM Positive and Negative Ion Calibration Solutions (Thermo Fisher Scientific). Run order of samples was randomized and technical replicates were injected after every 4 samples to assess quality control. Metabolite assignments and correction for expected natural abundances of 13C isotopes were performed using MAVEN."},

"MS_METABOLITE_DATA":{
"Units":"Peak Area",

"Data":[{"Metabolite":"Cytosine_C12 PARENT","1":"273769.78","2":"427328.34","3":"384665.66","4":"322014.38","5":"412568.25","6":"378301.72","7":"186471.36","8":"321558.41","9":"3126.82","10":"302902.97","11":"275340.91","12":"283378.97","13":"35760.92","14":"45012.78","15":"46522.46","16":"37934.88","17":"54252.36","18":"44077.36","19":"18659.93","20":"19398.63","21":"20635.76","22":"1718.01","23":"103020.02","24":"21733.90","37":"38420.59","38":"45778.47","39":"62389.89","40":"48536.92","41":"59659.39","42":"48028.45","43":"33890.61","44":"49019.06","45":"40232.26","46":"41075.07","47":"40024.24","48":"40359.52"},{"Metabolite":"Cytosine_N15-label-1","1":"0.00","2":"0.00","3":"0.00","4":"0.00","5":"0.00","6":"0.00","7":"0.00","8":"0.00","9":"0.00","10":"0.00","11":"0.00","12":"0.00","13":"847.42","14":"985.67","15":"1287.21","16":"994.01","17":"1406.40","18":"1076.25","19":"3084.16","20":"4168.79","21":"4131.90","22":"157.16","23":"3323.96","24":"5127.98","37":"665.92","38":"653.35","39":"887.89","40":"799.94","41":"791.56","42":"724.55","43":"586.98","44":"1843.46","45":"1593.96","46":"2148.40","47":"1053.40","48":"2786.00"},{"Metabolite":"N-carbamoyl-L-aspartate_C12 PARENT","1":"70096.59","2":"75015.65","3":"80411.03","4":"108302.25","5":"97993.03","6":"110788.91","7":"76196.59","8":"67345.72","9":"17624.87","10":"75534.58","11":"89830.21","12":"85082.47","13":"10542.82","14":"18641.14","15":"23634.35","16":"16480.72","17":"6941.88","18":"17663.41","19":"14758.68","20":"19266.46","21":"6781.26","22":"12074.52","23":"16489.78","24":"11372.47","37":"8710.08","38":"6494.02","39":"15334.67","40":"9410.74","41":"13026.77","42":"11228.59","43":"13292.68","44":"8439.98","45":"13190.40","46":"13893.60","47":"15672.25","48":"9225.72"},{"Metabolite":"N-carbamoyl-L-aspartate_N15-label-1","1":"0.00","2":"0.00","3":"0.00","4":"0.00","5":"0.00","6":"0.00","7":"0.00","8":"0.00","9":"0.00","10":"0.00","11":"0.00","12":"0.00","13":"2129.79","14":"2883.23","15":"6088.26","16":"2715.13","17":"3708.28","18":"2989.47","19":"11046.89","20":"10342.92","21":"6192.66","22":"141.18","23":"12328.59","24":"10381.61","37":"5815.79","38":"5293.30","39":"8420.35","40":"5830.32","41":"5950.32","42":"8308.47","43":"4096.89","44":"5667.49","45":"3279.13","46":"3168.72","47":"4337.29","48":"3431.16"},{"Metabolite":"thymidine_C12 PARENT","1":"842918.69","2":"825068.56","3":"765103.75","4":"886921.81","5":"882046.94","6":"878989.56","7":"1906071.00","8":"2218468.75","9":"167380.30","10":"2280389.00","11":"2258197.00","12":"2379568.00","13":"746333.94","14":"685091.75","15":"852261.44","16":"841343.69","17":"784131.75","18":"802866.00","19":"2320866.00","20":"2375094.25","21":"1925479.00","22":"36501.19","23":"410769.59","24":"2584070.25","37":"1183882.25","38":"1252127.88","39":"1144299.62","40":"1182820.12","41":"1272024.00","42":"1172009.62","43":"2109535.50","44":"2652011.25","45":"2645418.00","46":"2589102.25","47":"2320525.75","48":"2216848.75"},{"Metabolite":"thymidine_15N-label-1","1":"0.00","2":"0.00","3":"0.00","4":"0.00","5":"0.00","6":"0.00","7":"0.00","8":"0.00","9":"0.00","10":"0.00","11":"0.00","12":"0.00","13":"59.82","14":"3.93","15":"185.96","16":"83.18","17":"90.84","18":"59.28","19":"306.63","20":"588.02","21":"826.90","22":"79.45","23":"283.86","24":"1100.44","37":"51.67","38":"62.66","39":"80.43","40":"40.78","41":"67.98","42":"93.07","43":"171.63","44":"154.67","45":"181.91","46":"194.88","47":"178.59","48":"276.70"},{"Metabolite":"UMP_C12 PARENT","1":"147475.73","2":"111093.60","3":"123611.81","4":"145956.84","5":"199034.25","6":"132916.45","7":"170352.12","8":"168352.44","9":"78130.19","10":"174137.48","11":"237272.45","12":"213282.62","13":"28913.75","14":"30442.16","15":"22744.47","16":"32041.56","17":"16615.06","18":"34459.30","19":"10145.96","20":"7476.08","21":"13886.89","22":"3500.96","23":"8273.75","24":"6381.89","37":"10505.11","38":"4939.83","39":"14306.77","40":"11426.52","41":"11239.40","42":"10611.15","43":"34241.55","44":"32720.28","45":"51545.20","46":"49129.14","47":"61429.84","48":"35054.46"},{"Metabolite":"UMP_N15-label-1","1":"0.00","2":"0.00","3":"0.00","4":"0.00","5":"0.00","6":"0.00","7":"0.00","8":"0.00","9":"0.00","10":"0.00","11":"0.00","12":"0.00","13":"164.19","14":"193.22","15":"123.91","16":"488.03","17":"146.76","18":"472.36","19":"831.73","20":"1996.15","21":"1742.94","22":"1690.49","23":"1477.77","24":"1682.80","37":"133.26","38":"284.51","39":"517.55","40":"354.82","41":"197.46","42":"313.92","43":"666.27","44":"702.49","45":"409.26","46":"797.60","47":"1021.12","48":"371.12"},{"Metabolite":"aspartate_C12 PARENT","1":"1719268.62","2":"1845916.50","3":"1633825.62","4":"2146660.75","5":"1863445.62","6":"2360972.75","7":"420063.25","8":"322861.81","9":"965795.69","10":"428296.16","11":"407050.66","12":"420386.34","13":"15044.75","14":"16475.52","15":"16729.68","16":"18672.75","17":"16684.91","18":"17289.12","19":"12708.65","20":"12678.75","21":"12460.76","22":"9176.14","23":"14141.89","24":"9781.47","37":"17631.17","38":"23643.18","39":"23249.29","40":"16445.84","41":"23857.80","42":"23212.75","43":"17876.37","44":"14510.06","45":"186225.07","46":"23142.96","47":"20078.87","48":"16209.16"},{"Metabolite":"aspartate_N15-label-1","1":"0.00","2":"0.00","3":"0.00","4":"0.00","5":"0.00","6":"0.00","7":"0.00","8":"0.00","9":"0.00","10":"0.00","11":"0.00","12":"0.00","13":"17381.10","14":"14783.94","15":"12780.17","16":"17485.57","17":"17257.26","18":"15370.02","19":"15221.47","20":"13835.54","21":"22734.47","22":"12575.40","23":"13974.88","24":"13484.31","37":"19093.65","38":"21772.36","39":"21439.85","40":"23266.57","41":"21486.17","42":"29929.70","43":"24364.42","44":"10428.56","45":"22801.60","46":"25709.20","47":"19620.58","48":"26994.52"},{"Metabolite":"L-Asparagine_C12 PARENT","1":"2198123.00","2":"1885513.00","3":"2224036.00","4":"2197431.00","5":"2572088.00","6":"2054446.00","7":"2559641.00","8":"2388497.00","9":"1007695.00","10":"2659852.00","11":"2485501.00","12":"2737381.00","13":"18604.18","14":"21892.24","15":"21547.16","16":"23057.31","17":"18967.21","18":"20830.48","19":"69908.54","20":"76450.91","21":"64456.53","22":"12095.84","23":"66677.62","24":"75733.15","37":"58059.19","38":"40555.99","39":"49418.81","40":"47154.31","41":"42826.13","42":"47979.90","43":"57949.50","44":"57940.59","45":"59817.54","46":"59809.08","47":"60283.79","48":"53460.44"},{"Metabolite":"L-Asparagine_N15-label-1","1":"0.00","2":"0.00","3":"0.00","4":"0.00","5":"0.00","6":"0.00","7":"0.00","8":"0.00","9":"0.00","10":"0.00","11":"0.00","12":"0.00","13":"1269.49","14":"2173.94","15":"1428.38","16":"1969.46","17":"2294.73","18":"1494.71","19":"15574.07","20":"13520.13","21":"16415.92","22":"11467.49","23":"10993.08","24":"9774.55","37":"0.00","38":"0.00","39":"0.00","40":"3463.08","41":"0.00","42":"3990.96","43":"474.02","44":"0.00","45":"0.00","46":"731.24","47":"0.00","48":"331.63"},{"Metabolite":"Orotate_C12 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}

}