siRNAs for Anti-fibrotic Activity in Liver Disease

Dr. Rifaat Safadi

Hepatic-fibrosis is the end-stage consequence of chronic-liver-disease, affecting hundreds of million people worldwide. It is CD8-mediated-disease; in contrast, NK-cells have an anti-fibrotic activity through stimulation of killing of activated hepatic stellate cells (HSC), the fibrogenic cells in liver. Inhibitory/activating-killing-immunoglobulin-related-receptors and the aKIR:iKIR-ratio are significantly increased while Class-I expression by HSC is decreased. Small-interfering-RNAs (siRNAs) provide specificity to protein effectors complexes that repress mRNA transcription/translation. We hypothesize that siRNAs targeted to fibrogenic mediators will attenuate hepatic-fibrosis; siRNA candidates will include iKIR and other fibrotic mediators of CD8-subsets. In the proposed study, we will identify pro/anti-fibrotic genes expressed by lymphocyte-subset that reveal targets for antagonism using siRNA and evaluate the anti-fibrotic activity of siRNAs in liver-injury in-vitro and in-vivo. For this purpose, we will use the microarray assessment of mRNA extracts from different lymphocyte subsets. Each human lymphocyte subset transfected with specific siRNA will be co-cultured with human HSC and assess for fibrogenic activity. Each human-HSC transfected with a specific siRNA will be co-cultured with HCV/HBV lymphocytes and assessed for fibrogenic markers. The findings will implement for novel immunomodulatory strategies in patients with advanced liver disease.