Mechanobiology of Chronic Liver Disease:
Liver cirrhosis, the ultimate stage of advanced chronic liver disease (ACLD), is a leading cause of adult mortality in Europe. ACLD progression involves pro-fibrogenic changes in liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), leading to heightened vascular resistance and increased extracellular matrix deposition. Our project challenges current understanding by proposing that liver stiffness itself, influenced by mechanical forces, plays a pathophysiological role in perpetuating hepatic fibrosis. The study aims to elucidate the mechanistic link between extracellular matrix stiffness, intercellular communication, and nuclear tension, offering new insights into therapeutic strategies for ACLD.
Exploring novel therapeutic strategies for liver cirrhosis and portal hypertension:
Chronic liver disease (CLD) is responsible for over 2 million deaths worldwide each year, yet there are no approved medications for it. Carvedilol, a third-generation non-selective beta-blocker (NSBB), is a promising treatment that reduces portal pressure in cirrhotic patients by decreasing splanchnic circulation. However, how Carvedilol works within the liver is not well understood. Our project aims to investigate whether Carvedilol, beyond its known actions, enhances the liver's internal environment in cirrhosis by improving the function of liver sinusoidal endothelial cells (LSECs) and reducing the activation of hepatic stellate cells (HSCs).
Furthermore, our lab is exploring the impact of nanotechnology applications for the therapy of liver fibrosis. Silymarin (SMR) as other antifibrotic drugs, shows encouraging effects, but its limited bioavailability poses a challenge. In collaboration with Prof. Paola Luciani's Pharmacology department, we're combining phospholipids (EPLs) with SMR to enhance its hepatic uptake. Our focus is on understanding the anti-fibrotic effects of nanodrug administration such as the polyenylphosphatidylcholine (PPC) combined with SMR in advanced CLD.
Epigenetic Changes in Liver Fibrosis:
The development of effective anti-fibrotic therapies has been hindered, in part, by the inadequacy of traditional in vitro platforms in mimicking the complex pathophysiological conditions occurring in vivo. In response, our translational lab created a project to investigate how chromatin remodeling of liver cells differs in vitro and in vivo. By focusing on the epigenetic profile, we aim to uncover crucial upstream events that influence our understanding of the molecular processes underlying liver disease.
Mechanisms of fibrosis regression in cirrhosis:
Liver cirrhosis is a serious condition that can lead to severe complications, liver transplantation, and even death. Clinical studies support reversibility of cirrhosis upon removing the underlying injury. However, the mechanisms of fibrosis regression remain underexplored. Certain signaling pathways, like Hippo, hedgehog, notch, and Wnt, have been linked to fibrosis, and modifying their activity could potentially reverse the condition. However, this idea has not been thoroughly tested, and we also lack reliable markers to predict which patients will benefit from such treatment. This project aims to understand the mechanisms behind the regression of fibrosis in advanced chronic liver disease/cirrhosis. Understanding the role of potential novel pathways in fibrosis regression could lead to the development of targeted therapies that accelerate fibrosis resolution, which would have a profound impact by reducing the number of deaths, the need for liver transplants, the medical burden, economic costs, and suffering associated with chronic liver diseases.
