Giulia obtained my MSc degree cum laude in Environmental Sciences and Technologies at the University of Milano-Bicocca (Italy). Afterwards, she obtained her PhD in biology at the University of Milano-Bicocca in the Environmental sciences department, on a project aiming at improving the in vitro prediction of the carcinogenic potential of chemicals. After her PhD, she joined as post-doctoral researcher the Leiden Academic Leiden Center for Drug Research (LACDR) at Leiden University on a project aiming at establishing innovative methods to discover translational mechanistically relevant safety biomarkers for drug exposures (IMI eTRANSAFE project). During her postdoc, she developed the TXG-MAPr, a tool based on weighted gene co-regulated networks that aid the interpretation of toxicogenomics data to obtain a mechanistic-based risk assessment. After that, she joined Certara as scientist to work on a research project aiming at integrating non-animal approaches in regulatory toxicology, in particular brining expertise for omics innovation. Currently she is assistant professor at Leiden University, where she aims to progress the acceptance of omics technologies for chemical safety assessment and exploit network-based methods to improve our understanding of the mechanisms of action of drugs and to improve animal-to-human and in vitro-to-in vivo translation.
A Systems Approach to Elucidating Pathways of Liver Regeneration After Partial Hepatectomy and Ischemia Reperfusion Injury
Giulia Callegaro, Steven J. Kunnen, Bob van de Water, James Stevens
Recovery from liver injury depends on a balance between damage and repair processes. Herein, we used a transcriptomic approach and weighted gene co-expression network analysis (WGCNA) to investigate longitudinal responses during liver injury and regeneration in two models, partial hepatectomy (PHx) and a partial ischemia-reperfusion injury (IRI) model in which only the lateral lobes were rendered ischemic. Eigengene scores (EGS) for networks of genes (modules) with biologically meaningful enrichment provided quantitative measures of complex cellular processes associated with morphological evidence and functional markers of injury and repair allowing us to infer mechanisms of pathogenesis and recovery. Results suggest that after PHx, ribosome and mitochondrial biogenesis, along with hepatocellular hypertrophy, help stabilize hepatic function. These events precede proliferation of hepatocytes and recovery of liver mass. In the IRI model, morphology and transcriptomic responses from the non-ischemic lobe resembled PHx data. By contrast, necrosis and inflammation in the ischemic lobes were associated with a delay in morphological and molecular indicators of repair and regeneration despite rapid recovery of liver function, as reflected in serum total bilirubin levels. Similarity analysis using transcriptomic data showed that early (4 hr) transcriptional responses in the ischemic liver lobes resembled xenobiotic liver injury. However, within 12 hours the bulk of the signal in both lobes was dominated by tissue regeneration and repair responses. Our results provide an approach to reducing complex toxicogenomic data to mechanistic information associated with pathogenesis and highlight the impact of hepatic injury on adaptive and regeneration responses as well as generalizable liver responses to injury and repair.
