Farnesoid X Receptor Agonism, Apoptose Signaling Kinase 1 Inhibition and Acetyl-CoA Carboxylase Inhibition in Liver Cirrhosis and Portal Hypertensionr
Liver cirrhosis represents a major public health burden and the end-stage of various chronic liver diseases. In liver cirrhosis intrahepatic vascular resistance is increased, both due to functional and structural abnormalities, which leads to an elevation of blood pressure in the portal venous system. Portal hypertension becomes clinically significant when exceeding 10mmHg triggering the development of porto-systemic collaterals (e.g. esophageal varices), of hyperdynamic circulation, of hepatic encephalopathy, hepato-pulmonary syndrome or hepato-renal syndrome. Structural abnormalities in cirrhosis include vascular remodeling (capillarization of hepatic sinusoids) and tissue scarification. Functional abnormalities include sinusoidal vasoconstriction, due to an imbalance of vasodilators and vasoconstrictors, and further aggravated by endothelial hypo-responsiveness.
Since non-selective beta blockers represent by now the only medical therapy for portal hypertension novel treatment strategies are needed to pave the way to halt fibrosis progression, help fibrosis resolution and reversing the portal hypertensive syndrome. In preclinical studies different novel therapies are tested in animal models for portal hypertension and cirrhosis of different etiologies. Next to the evaluation of the therapeutically effects of these novel substances the cell-specific effects in primary non-parenchymal liver cells are tried to be deciphered. As a matter of course all methods for each evaluation process in-vivo and ex-vivo is in a continuously state of improvement.
In this doctoral thesis I will investigate the efficacy of the FXR agonist GS-9674, the ASK1 inhibitor GS-4793, the ACC inhibitor GS-834356 and combinations of these molecules on liver fibrosis and portal hypertension in an animal model of CCl4-induced toxic cirrhosis. Furthermore, I will evaluate the effect of ASK1 inhibition, ACC inhibition and FXR agonism on hepatic stellate cell activation and sinusoidal endothelial cell capillarization in vitro.
Methods and Skills:
Laboratory animal medicine; animal welfare, surgical interventions and anaesthesia; medical statistics; real-time PCR; cell culture; histology; tissueFax; diagnostic sonography/radiology and computer tomography
Königshofer P, Brusilovskaya K, Schwabl P, Podesser BK, Trauner M, Reiberger T: Invasive hemodynamic characterization of the portal-hypertensive syndrome in cirrhotic rats. Journal of Visualized Experiments, in press (accepted 01/2018)