To Investigate the Radio-Responses in Hepatoblast and Hepatocyte and Their Associations with Rild, and to Discover Novel Biomarkers for Rild Detection by Trans-Omics Analysis( I )

Radiotherapy (RT) has traditionally not been a major treatment modality for liver tumor because of the poor tolerance of liver tissue to radiation, but has become particularly important due to the use of stereotactic radiotherapy (SBRT) and charged particle therapy. However, RT not only eradicates the tumor, but also inevitably damages the normal liver surrounding the tumor, leading to the concerns of radiation-induced liver diseases (RILD). At present, there are few studies depicting the underlying mechanisms of RILD; thus, nowadays no pharmacologic interventions are available to ameliorate the RILD. Besides, the evaluation for RILD is performed by MRI or CT in clinics at several months after RT. There still lacks suitable biomarker for early detection of RILD. In this study, we utilize the induced pluripotent stem cell (iPSC) technique to obtain bipotential hepatoblast and well-differentiated mature hepatocyte which are the two main hepatic lineages found in liver tissues, and study the impacts of RT on hepatoblasts and hepatocytes. We aim to study the cell viability, DNA repair ability and cell-cycle progression to access their susceptibility to radiation; and to investigate whether RT directly triggers hepatoblast/hepatocyte undergo trans-differentiation and epithelial-mesenchymal transition or have to be assisted by paracrine signals releasing from mesenchymal cells. In addition, hepatoblast-like and mature hepatocyte will be obtained from residual liver tissues after partial hepatectomy to validate the cellular responses observed from iPSC-derived cells. To depict the underlying mechanism for RILD, liver tissues during disease progression will be analyzed for the transcriptome, proteome and lipidome, and compared to those obtained from iPSC-derived or isolated hepatocytes. Selection of potential biomarkers for early detection of RILD and identification of therapeutic targets for RILD amelioration will be achieved through the findings via trans-omics analysis.The specific aims of this project are1. To study the susceptibility of hepatocyte to radiation and its role in liver differentiation/fibrosis.2. To study the susceptibility of hepatoblasts to radiation and its role in liver differentiation/fibrosis.3. To validate the susceptibility to radiation from primary cultured hepatoblasts/hepatocyte.4. To investigate the RILD pathogenesis by multi-omics analysis for setting up a biomarker panel and for finding out potential antagonist targets.

Project ID:PC10907-1137
External Project ID:MOST109-2628-B182-008