TAZ and YAP in Non-Alcoholic Steatohepatitis and its Complications
TAZ and YAP in Non-Alcoholic Steatohepatitis and its Complications
批准号:
9473156
负责人:
Robert F. Schwabe
金额:
$66.41万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-01-01 至 2021-12-31
关键词:
AddressAffectAutomobile DrivingCell physiologyCellsCellular Metabolic ProcessCholesterolCirrhosisDataDevelopmentDietDiseaseEpidemicFDA approvedFatty LiverFatty acid glycerol estersFibrosisFunctional disorderGenesGeneticGrowthHepatocyteHumanHydroxymethylglutaryl-CoA reductaseIL27RA geneLiverLiver FibrosisLiver diseasesMalignant - descriptorMalignant neoplasm of liverMediatingMembraneMessenger RNAModelingMusObesityOncogenicOrganPPAR-betaPathway interactionsPatientsPharmaceutical PreparationsPhosphorylation SitePilot ProjectsPlayPrevalencePrimary carcinoma of the liver cellsProteinsPublishingRepressionRoleSignal TransductionTestingTherapeuticTranslationsTriglyceridesTumor InitiatorsUp-Regulationbasebiological systemschronic liver diseasefatty acid oxidationin vivointerestlipid biosynthesisnonalcoholic steatohepatitisnovelnovel therapeuticspreventresponsetherapeutic targettranscription factortumorubiquitin-protein ligaseuptake
中文摘要
非酒精性脂肪性肝炎(NASH)是全球慢性肝病的主要原因。这个
从轻度脂肪变性发展为NASH、纤维化和肝细胞病变的病理生理学
癌症(HCC)在很大程度上仍不为人所知,目前还没有FDA批准的治疗NASH的药物。
这两个PI最近发表了人类和小鼠Nash肝脏中肝细胞(HCs)升高的研究报告
转录因子TAZ水平和沉默HC TAZ抑制脂肪变性为NASH的纤维化
进步。自那以后,我们已经证明了密切相关的蛋白质YAP在NASH中也升高,并且HC
令人惊讶的是,YAP可以抑制脂肪变性、NASH和纤维化。我们还表明,高密度脂蛋白胆固醇
堆积是人类NASH的一个关键特征,它通过阻断蛋白酶体来增加HC TAZ/YAP
退化。最后,我们在NASH诱导的肝细胞癌中发现了高水平的TAZ/YAP,我们的初步研究表明
HC-TAZ沉默可防止NASH向肝细胞癌进展。这项建议的目的是探讨
假设胆固醇诱导的HC TAZ和YAP的升高调节了NASH的进展,
纤维化、肝细胞癌和TAZ可能是所有疾病阶段的治疗靶点。目标1
探索HC YAP如何抑制脂肪变性的机制和后果。我们将测试
假设HC YAP(A)部分抑制参与从头脂肪生成和甘油三酯合成的基因
通过HC YAP介导的PPAR的减少和(B)诱导与脂肪酸氧化有关的基因。到时候我们会的
验证以下假设:阻断HC YAP通过其促进脂肪变性的作用和可能通过
增加HC TAZ。我们还将测试在早期脂肪性肝病中强制表达HC-YAP是否可以
防止脂肪变性和进展为NASH。目的2探讨HC TAZ基因表达上调的机制
还有纳什的YAP。我们认为,由E3连接酶TrCP介导的TAZ/YAP蛋白酶体降解是
在NASH中被抑制,其机制涉及胆固醇在HCS中的积聚。我们假设
高密度脂蛋白膜胆固醇升高改变细胞信号以阻断TAZ和TZ上位点的磷酸化
YAP需要识别TrCP或直接抑制TrCP本身。目标3探讨了胆固醇的作用-
Taz/YAP通路在NASH诱导的肝癌中的作用我们假设胆固醇诱导的TAZ蓄积--两者
通过胆固醇摄取和HMG-CoA还原酶介导的途径促进肝癌的发展
高级纳什。我们将首先测试从NASH到肝癌的进展是否可以通过基因靶向来防止
如飞行员数据所建议的HC TAZ、HC YAP和HC TAZ+YAP。然后我们将检验以下假设:(A)
胆固醇诱导的HC-TAZ加速NASH-纤维化-肝癌序列;(B)胆固醇诱导的TAZ和
YAP还通过细胞自主机制推动启动肿瘤的HC的恶性转化;以及(C)
他汀类药物抑制TAZ/YAP和NASH诱导的肝癌。成功完成这些目标将提供至关重要的新的
帮助推进我们对NASH及其并发症的发现的治疗翻译的信息。
英文摘要
Non-alcoholic steatohepatitis (NASH) is the leading cause of chronic liver disease worldwide. The
pathophysiology that underlies the progression from bland steatosis to NASH, fibrosis, and hepatocellular
carcinoma (HCC) remains largely unknown, and there are currently no FDA-approved drugs to treat NASH.
The two PIs have recently published that hepatocytes (HCs) in human and mouse NASH liver have elevated
levels of the transcription factor TAZ and that silencing HC TAZ suppresses steatosis-to-NASH fibrosis
progression. We have since shown that the closely related protein YAP is also elevated in NASH and that HC
YAP, surprisingly, suppresses steatosis, NASH, and fibrosis. We have also shown that HC cholesterol
accumulation, a key feature of human NASH, increases HC TAZ/YAP by blocking their proteasomal
degradation. Finally, we found high levels of TAZ/YAP in NASH-induced HCC, and our pilot studies show that
HC-TAZ silencing prevents NASH-to-HCC progression. The objective of this proposal is to explore the
hypothesis that cholesterol-induced elevations in HC TAZ and YAP modulate the progression to NASH,
fibrosis, and HCC and that TAZ may represent a therapeutic target for all disease stages. Aim 1
explores the mechanisms and consequences of how HC YAP suppresses steatosis. We will test the
hypothesis that HC YAP (a) represses genes involved in de novo lipogenesis and triglyceride synthesis, in part
via HC YAP-mediated decrease in PPAR and (b) induces genes involved in fatty acid oxidation. We will then
test the hypothesis that blocking HC YAP promotes NASH fibrosis via its pro-steatotic actions and possibly by
increasing HC TAZ. We will also test whether forced expression of HC-YAP in early fatty liver disease can
prevent steatosis and the progression to NASH. Aim 2 investigates the mechanism of up-regulation of HC TAZ
and YAP in NASH. We propose that proteasomal degradation of TAZ/YAP mediated by the E3 ligase TrCP is
inhibited in NASH and the mechanism involves cholesterol accumulation in HCs. We hypothesize that
elevation of HC membrane cholesterol alters cell signaling to block the phosphorylation of sites on TAZ and
YAP required for TrCP recognition or directly inhibit TrCP itself. Aim 3 explores the role of the cholesterol-
TAZ/YAP pathway in NASH-induced HCC. We hypothesize that cholesterol-induced TAZ accumulation – both
via cholesterol uptake and HMG-CoA reductase-mediated pathways - promotes the development of HCC in
advanced NASH. We will first test if the progression from NASH to HCC can be prevented by genetic targeting
of HC TAZ, as suggested by pilot data, HC YAP, and HC TAZ + YAP. We will then test the hypotheses that (a)
cholesterol-induced HC-TAZ accelerates the NASH-fibrosis-HCC sequence; (b) cholesterol-induced TAZ and
YAP also drive malignant transformation in tumor-initiating HC via cell-autonomous mechanisms; and (c)
statins inhibit TAZ/YAP and NASH-induced HCC. Successful completion of these aims will provide critical new
information to help advance therapeutic translation of our discoveries for NASH and its complications.
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会议论文
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批准号:10612948
-
项目类别:
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-
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The Columbia University Digestive and Liver Disease Research Center
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依托单位:
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依托单位:
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Protective and fibrosis-independent functions of hepatic stellate cells
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依托单位:
Protective and fibrosis-independent functions of hepatic stellate cells
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Tumor-promoting and tumor-suppressive roles of Hepatic Stellate Cell Subpopulations in NASH-HCC
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Tumor-promoting and tumor-suppressive roles of Hepatic Stellate Cell Subpopulations in NASH-HCC
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依托单位:
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依托单位:
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批准号:10021026
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资助金额:$52.0万
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财政年份:2019
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负责人:Robert F. Schwabe
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依托单位:
FASEB SRC on Liver Biology: Fundamental Mechanisms and Translational Applications
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批准号:9121124
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HMGB1 as Link Between Hepatocellular Injury and HCC
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批准号:9888333
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资助金额:$44.38万
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财政年份:2016
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依托单位:
HMGB1 as Link Between Hepatocellular Injury and HCC
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批准号:9258403
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资助金额:$44.38万
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依托单位:
Hepatic Stellate Cells and Liver Cancer
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批准号:8801797
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资助金额:$37.02万
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批准号:9003035
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Promotion of Hepatocellular Carcinoma by Myofibroblasts
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批准号:8256908
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