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Modulation of liver fibrosis by liposome-mediated selective targeting of hepatic stellate cells (IWT619)

Chronic liver disease is a global health care problem. It develops as a consequence of chronic viral infections, drug or alcohol abuse, autoimmune disorders or as part of the metabolic syndrome. Independent of the causative factors, chronic liver injury leads to organ fibrosis and further develops to cirrhosis or hepatocellular carcinoma. Currently, no effective anti-fibrotic treatment is available and for nd-­?stage liver disease patients liver transplantation is the best chance for survival. Unfortunately, the availability of donor organs is insufficient and as the prevalence of liver diseases increases, other alternatives are urgently needed. Hepatic stellate cell activation has been identified as a key event in the development of fibrosis. During activation, quiescent vitamin. A storing pericytes transform into contractile myofibroblastic
cell in response to injury.These cells are the main cellular source for extracellular matrix and uncontrolled and continuous activation results in destruction of the organ structure and ultimately in organ failure. Many research efforts aimed to unravel and interfere with HSC activation in order to reduce or even reverse the fibrotic process. Encouraging results in in vitro and in vivo models for fibrosis have been obtained, but despite these efforts, no pharmacological agent has been approved for routine use in a clinical context of anti-­fibrotic therapy. Often, the use of promising therapeutics has to be discontinued due to development of severe side effects. The aim of our project is to develop targeted liposomes for delivery of therapeutic compounds or siRNAs, with a higher efficacy and less side effects. Specific molecules with affinity for receptors on the membrane of HSCs will be attached to the liposomal membrane in order to direct the liposomes to the target cells. Combining and comparing different lipid formulations and targeting molecules will allow the selection of the optimal liposomal formulation. Furthermore, the host lab demonstrated that liver sinusoidal endothelial cells (LSECs) take up part of the liposomes, resulting in off target effects in these cells. To prevent this we aim to block the scavenging function of these LSECs either by silencing scavenger receptor expression or by saturating the scavenger receptors. The effect and efficiency of these liposomes will be assessed in vivo in 2 mouse models for chronic liver injury. siRNAs for genes with an important role in HSC activation and already available compounds like sorafenib will be delivered and evaluated. In parallel with these studies, receptors as well as differentially expressed genes associated with the activated phenotype of human HSCs will be identified. Micro-­array data from human activated and quiescent HSCs are already available at the host lab.
Receptors associated with human activated HSCs will be used as novel targets for
liposomal delivery while novel potential pro-­fibrogenic genes will be evaluated
by siRNA-­?mediated silencing in cultured human cells. The techniques and tools developed in this project will be useful for already existing anti-­?fibrotic drugs that have too many side effects when systemically delivered but might also serve to silence pro-­?fibrotic genes in HSCs in the future. In order to accomplish this project we will collaborate with other labs for the following experiments; in vivo imaging analysis will be performed in collaboration with prof. T. Lahoutte (Medical Imaging and Physical Sciences, VUB), Micro-­array data were acquired in collaboration with Prof. R. Battaler and P. Sancho-­Bru (IDIBAPS, Spain) and Prof. P. Collas (UIO, Norway), characterization of the lipopolexes will be performed at the Ghent Research Centre on Nanopharmacy (Prof. S. De Smedt, UGent, Belgium).
We received human non-­parenchymal fractions from Prof. E. Sokal (UCL, Belgium).
Date:1 Jan 2013  →  4 Jun 2017
Keywords:Fibrosis, Hepatic Stellate Cells, Histon (de)acetylation, Stellate cell activation, Liver Cell Transplantation, Liver Sinusoidal Cells, Portal hypertension, Sinusoidal Cells, cirrhosis, Cytoskeleton, Cell Biology, Fat-Storing Cells, NASH / NAFLD, Intermediate Filaments, liver stem / progenitor cells, autophagy, Flow Cytometry, Metabolic Syndrome
Disciplines:Cytology, Morphological sciences, Immunology, Oncology, Systems biology, Multimedia processing