Dysregulation of Hepatic Energy Metabolism in Argininosuccinate Lyase Deficiency
Dysregulation of Hepatic Energy Metabolism in Argininosuccinate Lyase Deficiency
批准号:
9899983
负责人:
Lindsay C Burrage
金额:
$12.0万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-04-01 至 2021-03-31
关键词:
AddressAlanineAmmoniaArgininosuccinate lyase deficiencyAutomobile DrivingBiochemicalBiological ModelsBirthCell LineCell RespirationCell modelCellsChronicCirrhosisCitric Acid CycleClinicComplementComplicationDiseaseDisease modelEarly DiagnosisEnergy MetabolismEnzymesFibrosisFunctional disorderFutureGene ExpressionGenotypeHepaticHepatocyteHepatomegalyHereditary DiseaseHigh PrevalenceHyperammonemiaIn VitroIndividualInfantInvestigationKnowledgeLifeLinkLiverLiver DysfunctionLiver diseasesMeasuresModelingMusNatural HistoryNitrogenOxidative PhosphorylationOxidative StressPathogenesisPathway interactionsPatient CarePatientsPhenotypePortal HypertensionPrevalencePrimary carcinoma of the liver cellsPyruvateReagentResourcesRoleSeveritiesTestingTherapeuticTherapeutic StudiesTransaminasesUnited StatesUrea cycle disordersWild Type MouseWorkargininosuccinate lyasechronic liver diseasehepatocellular injuryhigh throughput screeningimprovedin vitro Modelin vivoinduced pluripotent stem cellinsightliver metabolismliver transplantationmitochondrial dysfunctionmouse modelnovelpreventstable isotopetargeted treatmenttherapeutic targeturea cycle
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
Urea cycle disorders are common inborn errors of liver metabolism. With improved therapies such as
nitrogen-scavenging agents to prevent elevated ammonia levels, patients with urea cycle disorders have
increased survival. However, even in the absence of hyperammonemia, patients with urea cycle disorders
(UCDs) may have chronic liver disease. This chronic liver disease appears to be more common in
argininosuccinate lyase deficiency (ASLD) as compared to other urea cycle disorders. The hepatic complications
in ASLD range from chronic hepatocellular injury, hepatomegaly, fibrosis, cirrhosis, and possibly hepatocellular
carcinoma. The pathogenesis for liver disease in ASLD and other UCDs remains unknown, and thus, there are
no specific therapies that target this complication.
As a first step towards developing therapeutic strategies targeting liver disease in ASLD and other UCDs,
we propose to investigate the biochemical basis of liver disease using a mouse model and newly developed
hepatocyte-like cell models for this disorder. Since the enzyme, argininosuccinate lyase, integrates two
fundamental pathways (urea cycle and citric acid cycle) in the cell, we hypothesize that energy dysregulation
results from citric acid cycle disruption and contributes to liver disease in ASLD. We plan to test this hypothesis
by pursuing studies that address the following questions: a) Is there mitochondrial dysfunction in the liver of the
ASL-deficient mice? b) Does citric acid cycle dysfunction contribute to energy dysregulation in hepatocyte-like
cells derived from patients with ASLD?
Overall, our studies will combine in vivo murine studies and studies in a new in vitro model to investigate the
link between the urea cycle, citric acid cycle and energy dysregulation. Our studies will enable the identification
of potential endpoints for future studies of therapeutic strategies for liver disease in ASLD and possibly other
UCDs. Moreover, the hepatocyte-like cells generated in this proposal will be an important resource for
performing high-throughput screening for therapeutic targets and for dissecting genotype-phenotype
relationships in ASLD. Lastly, on broader terms, these studies have the potential to yield important insights into
the role of energy dysregulation and urea cycle dysfunction in more common forms of liver disease.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
DISSECTING THE LINK BETWEEN UREAGENESIS AND HEPATIC GLYCOGEN METABOLISM
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批准号:10561730
-
项目类别:
-
资助金额:$46.38万
-
财政年份:2021
-
负责人:Lindsay C Burrage
-
依托单位:
DISSECTING THE LINK BETWEEN UREAGENESIS AND HEPATIC GLYCOGEN METABOLISM
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批准号:10094421
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项目类别:
-
资助金额:$46.1万
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财政年份:2021
-
负责人:Lindsay C Burrage
-
依托单位:
DISSECTING THE LINK BETWEEN UREAGENESIS AND HEPATIC GLYCOGEN METABOLISM
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批准号:10349428
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项目类别:
-
资助金额:$46.38万
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财政年份:2021
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负责人:Lindsay C Burrage
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依托单位:
BCM Center for Precision Medicine Models
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批准号:10670770
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项目类别:
-
资助金额:$198.76万
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财政年份:2020
-
负责人:Lindsay C Burrage
-
依托单位:
BCM Center for Precision Medicine Models
-
批准号:10875857
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项目类别:
-
资助金额:$16.0万
-
财政年份:2020
-
负责人:Lindsay C Burrage
-
依托单位:
Diversity Supplement: BCM Center for Precision Medicine Models
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批准号:10877479
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项目类别:
-
资助金额:$7.54万
-
财政年份:2020
-
负责人:Lindsay C Burrage
-
依托单位:
BCM Center for Precision Medicine Models
-
批准号:10259804
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项目类别:
-
资助金额:$198.95万
-
财政年份:2020
-
负责人:Lindsay C Burrage
-
依托单位:
Preclinical/Co-Clinical Section
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批准号:10471390
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项目类别:
-
资助金额:$25.48万
-
财政年份:2020
-
负责人:Lindsay C Burrage
-
依托单位:
Preclinical/Co-Clinical Section
-
批准号:10259806
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项目类别:
-
资助金额:$25.48万
-
财政年份:2020
-
负责人:Lindsay C Burrage
-
依托单位:
Preclinical/Co-Clinical Section
-
批准号:10670774
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项目类别:
-
资助金额:$26.28万
-
财政年份:2020
-
负责人:Lindsay C Burrage
-
依托单位:
BCM Center for Precision Medicine Models
-
批准号:10471388
-
项目类别:
-
资助金额:$198.95万
-
财政年份:2020
-
负责人:Lindsay C Burrage
-
依托单位:
Enhancing mouse embryo imaging capabilities at the BCM Center for Precision Medicine Models
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批准号:10808446
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项目类别:
-
资助金额:$33.85万
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财政年份:2020
-
负责人:Lindsay C Burrage
-
依托单位:
Clinical-Res-Project3
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批准号:10670165
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项目类别:
-
资助金额:$10.0万
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财政年份:2003
-
负责人:Lindsay C Burrage
-
依托单位:
Clinical-Res-Project3
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批准号:10241411
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项目类别:
-
资助金额:$10.0万
-
财政年份:2003
-
负责人:Lindsay C Burrage
-
依托单位:
Clinical-Res-Project3
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批准号:10018952
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项目类别:
-
资助金额:$10.0万
-
财政年份:2003
-
负责人:Lindsay C Burrage
-
依托单位:
Clinical-Res-Project3
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批准号:10463798
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项目类别:
-
资助金额:$10.0万
-
财政年份:2003
-
负责人:Lindsay C Burrage
-
依托单位:
Clinical-Res-Project3
-
批准号:9804383
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项目类别:
-
资助金额:$11.96万
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财政年份:--
-
负责人:Lindsay C Burrage
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依托单位:
海外基金