Jagged-Notch signaling in NASH/fibrosis
NASH/纤维化中的锯齿状Notch信号传导
基本信息
- 批准号:10338130
- 负责人:
- 金额:$ 41.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-15 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAttenuatedBiological MarkersBiopsyCCL2 geneCellsCessation of lifeCirrhosisCross-Sectional StudiesDataDecision MakingDevelopmentDietDiseaseDisease ProgressionES01EndosomesEyeFatty acid glycerol estersFibrinogenFibrosisGeneticGenetic TranscriptionGoalsHepaticHepatic Stellate CellHepatocyteHeterogeneityHumanImmuneInflammationInflammatoryInsulin ResistanceJAG1 proteinKnock-outLeadLigandsLiverLiver FibrosisMediatingMediator of activation proteinMembraneMetabolicMolecularMorbidity - disease rateMusObesityObesity EpidemicObservational StudyPathologyPathway interactionsPatientsPharmacologyPharmacotherapyPhenotypePioglitazonePlacebosPlasmaPlayPopulationPrevalencePrimary carcinoma of the liver cellsProcessProtein FamilyRecyclingRegulationReporterRoleSignal TransductionSteatohepatitisStimulusTestingTherapeuticTissuesToxic effectTranslationsUncertaintyVariantVimentinVitamin Ebiliary tractchronic liver diseasecomorbidityimprovedinhibitorliver biopsyliver inflammationliver injuryliver transplantationloss of functionmortalitymouse modelnicastrin proteinnon-alcoholic fatty liver diseasenon-diabeticnonalcoholic steatohepatitisnotch proteinnovelnovel markerobese patientsosteopontinreceptorrecruitresponsetranscriptome sequencing
项目摘要
Project Abstract
Obesity has multiple attendant metabolic comorbidities, including Non-Alcoholic Fatty Liver Disease (NAFLD).
NAFLD is now the leading cause of chronic liver disease, with prevalence approaching 30% in certain
populations, but may in fact be considered a “pre-disease” state for Non-Alcoholic Steatohepatitis (NASH).
NASH, defined by hepatocyte damage with associated inflammation and fibrosis, predisposes to cirrhosis and
hepatocellular cancer, and is the fastest-growing reason for liver transplantation. NASH has no approved
pharmacotherapy – as the prevalence of obesity-related NASH continues to rise, and available livers for
transplantation remain limiting, this unmet need grows more urgent.
Notch is a highly conserved family of proteins critical for cell fate decision-making, but less is known about
Notch action in mature tissue. Our initial characterization demonstrated that Notch activity is present at low
levels in normal liver, increases markedly in livers from obese patients and diet-induced or genetic mouse
models of obesity, but is highest in patients with NASH and shows significant positive correlations with plasma
ALT and NAFLD Activity Score. This observational study prompted a pilot sub-study of the PIVENS trial, where
we observed that improved NASH is associated with lower hepatic Notch activity. We next found that Notch
loss-of-function mice are protected from diet-induced steatohepatitis and fibrosis, whereas constitutively-active
hepatocyte Notch activity prompted inflammation and fibrosis even in chow-fed mice. Intriguingly, in NASH
patients and mouse models of steatohepatitis, expression of only 1 of 5 Notch ligands (Jag1) correlates with
disease pathology. These results suggest that Jag1-driven Notch activity in liver may be more than a
biomarker, but actually a mechanistic determinant of NASH/fibrosis, which we will test in this application. In
Aim 1, we study mechanistic determinants of increased Jag1 in the obese, inflamed liver, determine whether
hepatocyte Jag1 is necessary for increased liver Notch signaling in steatohepatitis and test whether novel Jag1
inhibitors may reduce obesity-induced liver inflammation and fibrosis. In Aim 2, we will test whether changes in
hepatocyte secretion of MCP1 and Osteopontin, both identified using an unbiased screen for markers of
Notch-active hepatocytes in mice with NASH, can explain Notch-mediated hepatic inflammation and fibrosis
respectively, as well as mechanism underlying Notch-induced transcription of these molecular mediators.
Achieving the goals of this application will identify the mechanism of increased hepatocyte Notch signaling in
the obese liver, delineate the mechanistic determinants of Notch-induced liver pathology and potentially lead to
application of novel Notch inhibitors for NASH and fibrosis.
项目摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Utpal Pajvani其他文献
Utpal Pajvani的其他文献
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{{ truncateString('Utpal Pajvani', 18)}}的其他基金
Beta cell Notch activity in Type 2 Diabetes
2 型糖尿病中的 Beta 细胞 Notch 活性
- 批准号:
10592434 - 财政年份:2022
- 资助金额:
$ 41.8万 - 项目类别:
Jagged-Notch signaling in NASH/fibrosis
NASH/纤维化中的锯齿状Notch信号传导
- 批准号:
10744371 - 财政年份:2019
- 资助金额:
$ 41.8万 - 项目类别:
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