To understand the function and regulation/dysregulation of angiogenesis in chronic liver disease
Angiogenesis is a hallmark of chronic liver disease that plays a major role within the liver, promoting inflammation, fibrogenesis and tumorigenesis, and also outside the liver, in splanchnic organs, contributing to the development of gastroesophageal varices and portal hypertension, which are clinically relevant complications of chronic liver disease. Therapeutic targeting of angiogenesis has been proposed as a promising strategy for chronic liver disease, including liver cirrhosis and liver cancer. However, the clinical benefit of antiangiogenic drugs is restricted because of significant adverse effects, including collapse of normal vasculature, vascular leakage and bleeding, as exemplified in patients with hepatocellular carcinoma and cirrhosis. Most of these limitations arise from the fact that current anti-angiogenic approaches are not selective for pathological neovessel production, but instead inhibit also physiological angiogenesis required for vascular homeostasis of healthy vessels and for processes like wound healing and tissue repair. Deciphering the molecular and cellular mechanisms that regulate/dysregulate angiogenesis in chronic liver disease is therefore critical to achieve specific inhibition of pathological neovascularization with beneficial therapeutic effects. This is a major goal of our group.
To explore the pathogenic mechanisms underpinning the detrimental impact of obesity in chronic liver disease
Over the last decades, obesity and its consequences have become a major health problem. Worldwide, more than 1 billion adults are overweight. The worst is that obesity does not only affect adults but also children. Obesity impacts on chronic liver disease by inducing liver steatosis and steatohepatitis, and by modifying the properties of intestinal microbiota and barrier and the functionality of visceral fat depots. Despite the clinical importance of the link obesity-liver disease, our understanding of the mechanisms underlying this relationship is extremely limited. This knowledge is crucial for advancements in treatment strategies for patients suffering from chronic liver disease. This is a major goal of our group.
To decipher the major disease-relevant pathways in the progression from liver steatosis to fibrosis and liver cancer
Liver cancer is among the most lethal and prevalent cancers worldwide, and the second most common cause for cancer-related death. In contrast to other cancers, its incidence is rising dramatically, and is predicted to increase even more in the coming years mainly due to the global epidemic of obesity/overweight, which has become a major socioeconomic challenge and strong risk factor for liver cancer. There is also an urgent need for development of novel therapeutic strategies to treat liver cancer. And for that it is essential to decipher mechanisms underpinning the detrimental impact of obesity on the progression of chronic liver disease, from simple steatosis to fibrosis and liver cancer, which are mostly still unknown. This is a major goal of our group.
To apply our knowledge and research discoveries on the fundamental cell biology/pathophysiology of liver disease to the comprehension, prevention or treatment of human pathologies
Chronic liver diseases are highly prevalent and associated with a high and dramatically increased burden worldwide. Despite that, development of new therapeutics remains stagnant. Liver transplantation currently represents the only chance of long-term survival for patients with chronic liver disease, but the availability of appropriate donor tissue is limited, and the procedure is highly expensive, necessitating a search for alternatives. Therefore, it is urgent to develop new strategies for diagnosis, prevention and treatment of chronic liver diseases. This is a major goal of our group. To this end, our team has established a working, highly collaborative and multidisciplinary relationship with world leading basic scientists, clinicians and bioinformaticians, with whom we have a high degree of connectivity and complementarity. This synergistic relationship allows us to achieve better outcomes and better opportunities to discover new druggable targets and innovative therapies for the treatment of chronic liver disease.
CPEB proteins regulate pathologic VEGF expression and angiogenesis
In a search for ways to inhibit pathologic production or activities of VEGF without affecting its normal production or functions, we have investigated the post-transcriptional regulation of VEGF by the cytoplasmic polyadenylation element-binding proteins CPEB1 and CPEB4 during development of liver disease. We have identified a mechanism of VEGF overexpression in liver and mesentery that promotes pathologic, but not physiologic, angiogenesis, via sequential and non-redundant functions of CPEB1 and CPEB4. Activation of CPEB1 promotes alternative nuclear processing within non-coding 3′-untranslated regions of VEGF and CPEB4 mRNAs, resulting in deletion of translation repressor elements. The subsequent overexpression of CPEB4 promotes cytoplasmic polyadenylation of VEGF mRNA, increasing its translation and generating high levels of VEGF protein, which induces pathologic angiogenesis in chronic liver disease (Read More).
CPEB proteins as targets for therapy
From a translational point of view, our studies highlight that CPEBs could be promising angiogenesis-disrupting targets in disease. Thus, targeting CPEBs could lead to safer treatment outcomes by specifically reducing excessive pathological VEGF production instead of indiscriminately perturbing both pathological and physiological VEGF synthesis, minimizing potential adverse side-effects. Reduction of pathological angiogenesis in early disease stages could also prevent further disease progression and reduce the risk for developing overt liver cirrhosis. Accordingly, development and evaluation of CPEB inhibitors is currently underway. As better and more specific inhibitors of pathologic angiogenesis are developed, combination strategies continue to evolve, and increased understanding of the complex biology of angiogenesis takes place, antiangiogenic therapy will certainly be evaluated in future clinical trials (Read More).