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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Dean Thiel Postdoctoral Research Fellowship Award
Cleveland Clinic, Cleveland, Ohio
Adenosine signaling pathway in the regulation of hepatic angiogenesis and fibrogenesis
Dr. Dian Chiang recognizes the initiation and perpetuation of hepatic fibrogenesis is a complex dynamic injury response in the liver that results in the transformation of hepatic stellate cells (HSC) into proliferative and fibrogenic myofibroblast-like cells which leads to ECM deposition. No effective anti-fibrosis treatment is currently available. Angiogenesis and the disruption of normal liver vasculature are linked to the progression of cirrhosis in chronic liver diseases and may contribute to the initiation of fibrogenesis. The insight of the link between angiogenesis and fibrogenesis may provide a novel approach for anti-fibrosis treatment. Adenosine signaling pathway is critical in the angiogenesis response to tissue injury and is involved in HSC activation as well as the development of hypoxia preconditioning in hepatocytes.
Thus, adenosine receptors and its downstream pathways are critical in hepatic angiogenesis and fibrogenesis. Adenosine type 2A receptor (A2A receptor) antagonist may be a potential treatment for liver fibrosis. The primary objective of Dr. Chiang’s proposal is to investigate the molecular regulatory link of pathological angiogenesis and fibrogenesis in the liver using a novel mouse model of ethanol and CCl4 exposure and to determine the therapeutic benefit of A2A receptor antagonist in preventing liver fibrosis by restoring the impaired injury response. Two novel pre-clinical mouse models of ethanol induced exacerbation of liver fibrosis will be applied in this study including an acute model to study the intermediate biomarkers involved in the initiation of angiogenesis and fibrogenesis induced by ethanol in response to a single CCl4 injection and a chronic model to assess ethanol enhanced HSC activation and liver fibrosis after bi-weekly CCl4 injections. In addition, A2A receptor antagonist will be used as an intervention to determine its effect on the angiogenesis response as well as its therapeutic efficacy in decreasing ethanol induced exacerbation of liver fibrosis in response to a second hepatotoxin, CCl4. Dr. Chiang hypothesizes that ethanol exposure increases extracellular adenosine, which signals through the A2A receptor and activates the downtream PI3K/PKB/HIF-1α pathway and results in increased expression of cytokines that promote angiogenesis and fibrosis. Further, he hypothesizes that ethanol increases PTEN mRNA transcription through the activation of EGR-1 and p53 and decreases PTEN degradation in the acute phase. PTEN may counter regulate or balance the A2A receptor activation and the PI3K/PKB/HIF-1α pathway initially and the subsequent loss of PTEN function in the chronic phase may lead to a self-perpetuating process of angiogenesis and fibrogenesis.
The results of Dr. Chiang’s the study will provide critical insight into the molecular regulation of angiogenesis and fibrogenesis in liver injury as well as pre-clinical data regarding the therapeutic benefit of a novel anti-fibrosis treatment.