Role of Intestinal Bile Acid Signaling in Liver Diseases
肠胆汁酸信号在肝脏疾病中的作用
基本信息
- 批准号:10257976
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-10-01 至 2025-09-30
- 项目状态:未结题
- 来源:
- 关键词:Alcoholic Liver DiseasesAnimal ModelAnimalsApoptosisAutomobile DrivingBile Acid Biosynthesis PathwayBile AcidsBiological MarkersCancer EtiologyCell ProliferationCessation of lifeCholestasisCholic AcidsCirrhosisDataDeoxycholic AcidDetergentsDevelopmentEarly DiagnosisEndocrineEnterohepatic CirculationEventFGF19 geneFibroblast Growth FactorFutureGoalsGrowthHealth BenefitHomeostasisHormonesHumanIntestinesKnock-outKnockout MiceLiverLiver RegenerationLiver diseasesMediatingMedicalMolecularMusPathogenesisPathologyPathway interactionsPatientsPhysiologyPlayPrevalencePreventionPrimary carcinoma of the liver cellsPropertyResearchRodentRoleSignal TransductionSomatotropinTestingTimeTransgenic MiceTransgenic OrganismsTumor Suppressor ProteinsVeteransbasecell injurychronic liver diseasecytotoxicdiagnostic biomarkerdrug induced liver injuryeffective therapyhormonal signalsin vivoinnovationmilitary veteranmouse modelnon-alcoholic fatty liver diseasenoveloverexpressionpatient populationpreventreceptorreceptor expressionreceptor functiontumor
项目摘要
PROJECT SUMMARY
The prevalence of cirrhosis and decompensated liver disease has doubled, whereas the prevalence of
hepatocellular carcinoma (HCC) has increased 10-fold in the veteran population. Worldwide, HCC has
emerged as a major cause of cancer-related death. There is an urgent need to further understand HCC
pathogenesis and discover new biomarkers that could accurately predict HCC development in patients with
chronic liver diseases, so that we can provide better and more effective strategies for HCC prevention and/or
treatment in veteran population. Bile acids (BAs) are well known to be cytotoxic due to their detergent-like
properties and overt BAs promote HCC development. In humans, increased levels of secondary BAs,
especially deoxycholic acid, is associated with the development of HCC in veteran patients with cirrhosis. BA
homeostasis is tightly regulated by farnexoid X receptor (FXR). FXR expression and function are reduced in
patients with HCC, and FXR knockout (KO) mice develop spontaneous HCC. FXR suppresses BA levels
mainly by fibroblast growth factor 15 (FGF15; FGF19 in humans) mediated gut liver crosstalk and by promoting
BA enterohepatic circulation. FGF15/19 emerges to be critical endocrine hormones to suppress BA synthesis,
promote liver regeneration and regulate energy homeostasis. Long-term overexpression of FGF15 in vivo
(Fgf15 transgenic-Tg mice) results in reduced growth hormone (GH) signaling in the liver and GH signaling is
involved in cell proliferation and HCC formation. In this proposal, we will determine the mechanisms by which
long-term FGF15 overexpression protects the liver from HCC development in FXR KO mice. Using a novel
mouse model we generated, Fgf15 Tg mice, and the newly generated FXR KO/Fgf15 Tg mice, we provided
preliminary data showing that FGF15 overexpression completely protected FXR KO mice from developing
spontaneous HCC. In addition, overexpression of FGF15 led to a marked reduction in BA levels and GH
signaling. Based on these compelling preliminary data, we generate a novel hypothesis: overexpression of
FGF15 prevents HCC development through two interactive mechanisms: suppression of BA levels and
reduction of GH signaling to reduce cell injury and cell proliferation. This novel hypothesis will be tested in two
independent but related specific aims. Aim 1. Determine to what extent reduction of BAs is the mechanism for
suppressing HCC development in cholestasis mouse models. Aim 2. Determine the extent of GH signal
blockage, and to what extent the reduced GH signal in the Fgf15 Tg mice prevents HCC development. This
proposal is highly innovative because we will provide a profound understanding of the molecular mechanisms
by which endocrine FGF15 collectively suppresses BA levels and GH signaling, which can markedly prevent
HCC development during cholestasis. It is also very technically innovative due to the unique and novel animal
models we have generated for in vivo studies. Furthermore, we will provide profound understanding of the
mechanisms of BA homeostasis, liver growth and HCC development. This study will be highly human relevant
because humans and rodents share similar BA pathways in liver disease development. We believe that this
study will help to provide scientific basis for prevention, early diagnosis, and treatment of human HCC
development in cirrhotic veteran patients in the future.
项目总结
肝硬变和失代偿性肝病的患病率翻了一番,而
在退伍军人中,肝细胞癌(肝细胞癌)的发病率增加了10倍。在世界范围内,肝癌已经
成为癌症相关死亡的主要原因。迫切需要进一步了解肝细胞癌
发病机制和发现新的生物标志物可以准确预测肝癌的发展
慢性肝病,以便为肝癌的预防和/或提供更好和更有效的策略
在退伍军人群体中进行治疗。众所周知,胆汁酸(BA)具有细胞毒性,因为它们类似洗涤剂。
属性和显性基础促进了肝细胞癌的发展。在人类中,次级bas水平增加,
尤其是脱氧胆酸,与老年肝硬变患者肝细胞癌的发生有关。基数
动态平衡受到法尼索X受体(FXR)的严格调控。FXR的表达和功能在
肝癌患者和FXR基因敲除(KO)小鼠发生自发性肝癌。FXR抑制BA水平
主要通过成纤维细胞生长因子15(FGF15;人类中的FGF19)介导的肠肝串扰和促进
BA肠-肝循环。FGF15/19是抑制BA合成的关键内分泌激素,
促进肝脏再生,调节能量平衡。成纤维细胞生长因子15在体内的长期过表达
(Fgf15转基因-TG小鼠)导致肝脏中生长激素(GH)信号的减少,GH信号是
参与细胞增殖和肝细胞癌的形成。在这项提案中,我们将确定通过哪些机制
在FXR KO小鼠中,长期过表达FGF15可以保护肝脏免受肝癌的发展。用一本小说
我们建立的小鼠模型,Fgf15 TG小鼠,以及新生成的FXR KO/Fgf15 TG小鼠,我们提供
初步数据显示FGF15过表达完全保护FXR KO小鼠发育
自发性肝癌。此外,FGF15的过度表达导致BA水平和GH水平显著下降
发信号。基于这些令人信服的初步数据,我们产生了一个新的假设:过度表达
FGF15通过两种相互作用机制预防肝癌的发生:抑制BA水平和
减少生长激素信号转导,减轻细胞损伤和细胞增殖。这一新的假设将分两个阶段进行检验
独立但相关的具体目标。目标1.确定在多大程度上降低BAS是
抑制胆汁淤积症小鼠肝癌的发展。目的2.确定生长激素信号的幅度
阻断,以及Fgf15转基因小鼠中生长激素信号的减少在多大程度上阻止了肝癌的发展。这
该提议具有很高的创新性,因为我们将提供对分子机制的深刻理解
通过内分泌FGF15共同抑制BA水平和GH信号,可以显著防止
肝细胞癌在胆汁淤积期的发展。由于独特而新颖的动物,它在技术上也非常创新
我们为活体研究建立的模型。此外,我们还将深入了解
BA动态平衡、肝脏生长和肝细胞癌发生的机制这项研究将与人类高度相关
因为人类和啮齿动物在肝脏疾病的发展过程中有着相似的BA途径。我们相信这一点
本研究将为人类肝癌的预防、早期诊断和治疗提供科学依据
肝硬变老兵未来的发展。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('GRACE L GUO', 18)}}的其他基金
Gut-liver crosstalk by FGF15/19 in regulating xenobiotic nuclear receptor activation
FGF15/19 调节外源性核受体激活的肠肝串扰
- 批准号:
10207687 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Gut-liver crosstalk by FGF15/19 in regulating xenobiotic nuclear receptor activation
FGF15/19 调节外源性核受体激活的肠肝串扰
- 批准号:
10286769 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Gut-liver crosstalk by FGF15/19 in regulating xenobiotic nuclear receptor activation
FGF15/19 调节外源性核受体激活的肠肝串扰
- 批准号:
10606597 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Gut-liver crosstalk by FGF15/19 in regulating xenobiotic nuclear receptor activation
FGF15/19 调节外源性核受体激活的肠肝串扰
- 批准号:
10386929 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Gut-liver crosstalk by FGF15/19 in regulating xenobiotic nuclear receptor activation
FGF15/19 调节外源性核受体激活的肠肝串扰
- 批准号:
10601255 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Role of Intestinal Bile Acid Signaling in Liver Diseases
肠胆汁酸信号在肝脏疾病中的作用
- 批准号:
10621137 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Gut bile acids, Fxr, & Fgf15 in total parenteral nutrition-associated cholestasis
肠胆汁酸,Fxr,
- 批准号:
8421637 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Gut bile acids, Fxr, & Fgf15 in total parenteral nutrition-associated cholestasis
肠胆汁酸,Fxr,
- 批准号:
8697069 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Gut bile acids, Fxr, & Fgf15 in total parenteral nutrition-associated cholestasis
肠胆汁酸,Fxr,
- 批准号:
9066738 - 财政年份:2013
- 资助金额:
-- - 项目类别:
FXR, nuclear receptors, and transcriptional regulation of liver homeostasis
FXR、核受体和肝脏稳态的转录调节
- 批准号:
8328025 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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