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Prediction and Prevention of Hepatic Decompensation in Patients with Cirrhosis

Prediction and Prevention of Hepatic Decompensation in Patients with Cirrhosis
肝硬化患者肝功能失代偿的预测和预防
批准号:
10700075
负责人:
Cynthia A Moylan
金额:
$26.49万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-20 至 2026-07-31
关键词:
3-hydroxy-3-methylglutaryl-coenzyme AAddressAdultAlcohol-Induced DisordersAlcoholsAnti-Inflammatory AgentsBile AcidsBiliaryCaringCessation of lifeCholesterolCirrhosisClinicalClinical ResearchCoenzyme ACommunitiesComplementDefectDevelopmentDiagnostic radiologic examinationEndoscopyEnzymesEvolutionFibrosisFunctional disorderGrowthHIV therapyHIV/AIDSHealthHealth systemHepaticHepatocyteHepatologyHumanHuman ResourcesHydroxymethylglutaryl-CoA Reductase InhibitorsHydroxymethylglutaryl-CoA reductaseImpairmentIndividualInflammatoryInjuryInstitutionIntervention TrialInterventional radiologyKnowledgeLiverLiver CirrhosisLiver DysfunctionLiver FailureLiver RegenerationLiver diseasesLiver parenchymaLongitudinal cohort studyMalignant NeoplasmsMalignant neoplasm of liverMedicalMedical OncologyMetabolicMetabolic syndromeMetabolismMorbidity - disease rateNatural regenerationNorth CarolinaObesityOperative Surgical ProceduresOrganOrgan failureOutcomeOxidoreductasePathologyPathway interactionsPatientsPersonsPharmaceutical PreparationsPlayPopulationPositioning AttributePre-Clinical ModelPreventionPrimary Health CareRegenerative pathwayResearchRiskRoleRural PopulationSafetyServicesSeveritiesSignal PathwaySuburban PopulationTestingTherapeuticTissuesUnited StatesUrban PopulationViral hepatitisWorkantiretroviral therapycancer riskcare providerscell typecomorbiditydemographicsdisability-adjusted life yearsdrug induced liver injuryeffective therapyefficacy evaluationfunctional lossgeranylgeranyl pyrophosphatehigh riskimprovedimproved outcomeinhibitorliver functionliver injuryliver preservationliver transplantationmevalonatemodifiable riskmortalitymultidisciplinarynon-alcoholic fatty liver diseasenovel strategiesolder patientpersonalized approachpersonalized medicinepre-clinical researchpreventproblem drinkerprogramsregenerativerepairedsuccess

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中文摘要
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ASTRACT
英文摘要
ASTRACT Liver cirrhosis and its complications cause significant morbidity and mortality in the United States. Cirrhosis and cirrhosis-related mortality are rising in parallel with shifts in the demographics driven by increases in alcoholic- and nonalcoholic- fatty liver disease. Current cirrhotic populations are enriched with older patients with damage in other tissues caused by obesity, the metabolic syndrome, and/or alcohol. These factors confound cirrhosis management and often preclude liver transplantation as a therapeutic option. Consequently, the number of patients with decompensated cirrhosis is growing. Hepatic decompensation results from loss of functional liver parenchyma and the severity of liver dysfunction is a proven-predictor of cirrhosis-related morbidity and mortality. Therefore, our overall objective is to develop novel approaches to preserve liver function and prevent hepatic decompensation in cirrhosis. Success necessitates more information about: i) modifiable risks that drive hepatic dysfunction and ii) how hepatic dysfunction impacts the health of other organs. To address these gaps in knowledge, we will conduct a longitudinal cohort study of patients with cirrhosis (Aim 1) and develop/implement an interventional trial using an HMG CoA reductase inhibitor (statin) in cirrhotic patients who are at high risk for hepatic decompensation. Both aims are grounded by the scientific premise that cirrhosis is caused by defective, maladaptive liver regeneration. Our pre-clinical research: i) reveals that liver regeneration requires tightly scripted reactivation of developmental signaling pathways that were once thought to be silenced in adult livers (but known to reactivate in cancer) and ii) shows that when these pathways become dysregulated, they impair regeneration and drive liver disease to progress to cirrhosis and cancer. These findings explain why organ failure, fibrosis and cancer risk typically evolve in parallel and justify research in human cirrhotic populations to identify factors that impact the regenerative mechanisms (Aim1). They also provide a strong conceptual basis for evaluating the ability of statins to improve liver function in cirrhosis (Aim2) because statins have anti-inflammatory and metabolic actions that are predicted to favorably modulate regenerative pathways. The Duke Liver Program is ideally-positioned for membership in the new Cirrhosis Clinical Network which will be configured to accomplish these aims: our multidisciplinary team of providers cares for a large, diverse cirrhotic population and we have had strong institutional support to develop outstanding programs in liver disease research and personalized medicine. Successful accomplishment of our Aims will enable a more ‘personalized’ approach to management that will improve cirrhosis outcomes despite challenging co-morbid conditions.
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Applying an 'omics' approach to predict hepatic decompensation events and hepatocellular carcinoma in veterans after HCV cure with direct acting antiviral therapy
  • 批准号:
    10260234
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2021
  • 负责人:
    Cynthia A Moylan
  • 依托单位:
Applying an 'omics' approach to predict hepatic decompensation events and hepatocellular carcinoma in veterans after HCV cure with direct acting antiviral therapy
  • 批准号:
    10548114
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2021
  • 负责人:
    Cynthia A Moylan
  • 依托单位:
海外基金