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: 9293341
• 负责人: Leila Gobejishvili
• 金额: $ 18.86万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9293341
• 关键词: Address; Attenuated; Centers of Research Excellence; Cirrhosis; Collagen; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DNA Modification Process; Development; Enzymes; Epigenetic Process; Etiology; FDA approved; Family; Fibrosis; Funding; Genes; Genetic Transcription; Hepatic Stellate Cell; Hepatocyte; In Vitro; Inflammation; Injury; Knockout Mice; Liver Fibrosis; Mass Spectrum Analysis; Mediating; Modeling; Modification; Morphology; Myofibroblast; PDE4B; Pathogenicity; Peroxisome Proliferator-Activated Receptors; Phenotype; Phosphorylation; Play; Post-Translational Protein Processing; Prevention strategy; Primary carcinoma of the liver cells; Process; Promoter Regions; Protein Isoforms; Proteins; Proteomics; Rattus; Regulation; Role; Rolipram; Second Messenger Systems; Signal Transduction; Therapeutic; Toxicology; Transcriptional Activation; Wound Healing; base; cell transformation; cytokine; experimental analysis; histone modification; in vivo; inhibitor/antagonist; liver injury; member; phosphodiesterase IV; promoter; translational study

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