kondevans2010 · Characterisation of early cellular and molecular alterations leading to inflammation and HCC using a mouse model with liver cell-specific NEMO ablation

Chronic liver inflammation has been shown to promote hepatocellular carcinoma (HCC). However, the initial cellular and molecular events that trigger the inflammation are largely unknown. The proposed study will provide a detailed characterisation of cellular processes that need to be deregulated in liver cells to cause inflammation. For this purpose, a genetic mouse model that closely reproduces all the stages of inflammation-related HCC will be used. This mouse exhibits a Liver Parenchymal Cell specific NEMO ablation (NEMOLPC-KO), the regulatory subunit of the IKK complex that activates NF-kB signalling.The two main goals of the proposed project are to a) unravel early cellular and molecular alterations in the liver cells of NEMOLPC-KO mice, and distinguish these resulting from a cell-autonomous effect of NEMO deletion from those resulting from a non-cell autonomous effect due to the inflammatory microenvironment and b) distinguish between NF-kB-dependent and independent functions of the NEMO/IKK complex in liver homeostasis.Two experimental strategies will be used to achieve these goals. The first is a targeted examination of specific cellular processes that could be implicated in the development of liver inflammation, such as the mitochondrial functions, ER stress, autophagy, and p62 functions. A combination of mouse genetics with cutting-edge microscopy and other cell biology techniques will be employed. The second involves high-throughput approaches, such as gene expression microarray, that will help distinguishing between the above-mentioned NEMO functions.The scientific impact of this study will be to define early cellular changes can disrupt liver cell homeostasis resulting in human liver inflammatory diseases, thus helping in development of new therapeutic approaches. Finally, the project will greatly benefit the applicant’s professional maturity that is important for pursuing an independent research career.