Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
PDE4 在肝星状细胞活化和 TGF 信号传导中的致病作用
基本信息
- 批准号:9293341
- 负责人:
- 金额:$ 18.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AddressAttenuatedCenters of Research ExcellenceCirrhosisCollagenCyclic AMPCyclic AMP-Dependent Protein KinasesDNA Modification ProcessDevelopmentEnzymesEpigenetic ProcessEtiologyFDA approvedFamilyFibrosisFundingGenesGenetic TranscriptionHepatic Stellate CellHepatocyteIn VitroInflammationInjuryKnockout MiceLiver FibrosisMass Spectrum AnalysisMediatingModelingModificationMorphologyMyofibroblastPDE4BPathogenicityPeroxisome Proliferator-Activated ReceptorsPhenotypePhosphorylationPlayPost-Translational Protein ProcessingPrevention strategyPrimary carcinoma of the liver cellsProcessPromoter RegionsProtein IsoformsProteinsProteomicsRattusRegulationRoleRolipramSecond Messenger SystemsSignal TransductionTherapeuticToxicologyTranscriptional ActivationWound Healingbasecell transformationcytokineexperimental analysishistone modificationin vivoinhibitor/antagonistliver injurymemberphosphodiesterase IVpromotertranslational study
项目摘要
Liver injury of different etiologies leads to a wound healing process involving activation of hepatic stellate cells
(HSCs). However, an ongoing hepatocyte injury and inflammation results in an uncontrolled activation and
proliferation of HSCs and development of hepatic fibrosis leading to cirrhosis and even hepatocellular cancer.
Despite the advances made, gaps remain in our understanding of the mechanisms involved in the process of
HSC transformation from quiescent to activated phenotype. Recently, we discovered that the
phosphodiesterase 4 (PDE4) subfamily of enzymes play a pathogenic role in the development of cholestatic
liver injury and fibrosis. Notably, PDE4s are not present in quiescent HSCs and are rapidly induced upon
activation in vitro. Further, the PDE4 specific inhibitor, rolipram, effectively attenuates ¿SMA, collagen
expression and accompanying morphological changes in HSCs. PDE4 is the largest sub-family among cAMP-
hydrolyzing PDEs, which tightly regulate the levels of cellular cAMP. cAMP, through its effector molecules
protein kinase A (PKA) and Exchange Protein directly Activated by cAMP (EPAC), has been shown to down-
regulate cytokine induced fibrogenic genes in non-hepatic cells. Hence, we hypothesize that induction of PDE4
expression and activity plays a causal role in HSC activation by decreasing cAMP-PKA/EPAC activities and
promoting fibrogenic signaling. We postulate that during HSC activation, promoter associated epigenetic
changes and post-translational modifications play a significant role in the regulation of PDE4 expression and
activity. We also postulate that PDE4 inhibition will restore PKA/EPAC activities and attenuate TGF¿-Smad
signaling through: (i) inactivation of relevant MAPKs; and (ii) de-repressing PPAR¿ leading to decreased
expression of ¿SMA and Col1A1. Importantly, inhibition of PDE4 activity may be a significant therapeutic
approach for liver fibrosis. The specific aims of this proposal are to: 1) Determine the role of PDE4 in the
regulation of fibrogenic signaling in HSCs; 2) Determine promoter-associated epigenetic modifications
contributing to the induction of PDE4 isoforms during HSC activation; and 3) Determine the post-translational
modifications (PTMs) relevant for PDE4 isoform function during HSC activation. Importantly, the results of this
COBRE-funded project will provide proof-of-principle and mechanistic rationale for in vivo translational studies
(R01) to examine PDE4 targeted strategies for prevention and treatment of hepatic fibrosis.
不同病因的肝损伤导致涉及肝星状细胞活化的伤口愈合过程
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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Leila Gobejishvili其他文献
Leila Gobejishvili的其他文献
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{{ truncateString('Leila Gobejishvili', 18)}}的其他基金
Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
磷酸二酯酶 4 介导的酒精相关性肝病的致病机制
- 批准号:
10877329 - 财政年份:2021
- 资助金额:
$ 18.86万 - 项目类别:
Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
磷酸二酯酶 4 介导的酒精相关性肝病的致病机制
- 批准号:
10491252 - 财政年份:2021
- 资助金额:
$ 18.86万 - 项目类别:
Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
磷酸二酯酶 4 介导的酒精相关性肝病的致病机制
- 批准号:
10661056 - 财政年份:2021
- 资助金额:
$ 18.86万 - 项目类别:
Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
磷酸二酯酶 4 介导的酒精相关性肝病的致病机制
- 批准号:
10345684 - 财政年份:2021
- 资助金额:
$ 18.86万 - 项目类别:
Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
磷酸二酯酶 4 介导的酒精相关性肝病的致病机制
- 批准号:
10738641 - 财政年份:2021
- 资助金额:
$ 18.86万 - 项目类别:
Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
PDE4 在肝星状细胞活化和 TGF 信号传导中的致病作用
- 批准号:
8813881 - 财政年份:2016
- 资助金额:
$ 18.86万 - 项目类别:
The role of hepatocyte cAMP/PDE4 in alcohol-induced liver steatosis and injury
肝细胞cAMP/PDE4在酒精性肝脂肪变性和损伤中的作用
- 批准号:
8638593 - 财政年份:2014
- 资助金额:
$ 18.86万 - 项目类别:
The role of hepatocyte cAMP/PDE4 in alcohol-induced liver steatosis and injury
肝细胞cAMP/PDE4在酒精性肝脂肪变性和损伤中的作用
- 批准号:
8798551 - 财政年份:2014
- 资助金额:
$ 18.86万 - 项目类别:
Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
PDE4 在肝星状细胞活化和 TGF 信号传导中的致病作用
- 批准号:
9904707 - 财政年份:
- 资助金额:
$ 18.86万 - 项目类别:
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