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Project
Exploring the initiation and progression of NASH in a stem cell derived liver coculture model by revealing cellular stress activation pathways in real time (FWOTM1107)
Non-alcoholic fatty liver disease (NAFLD) still remains a devastating
condition with no approved pharmaceutical therapy. To date, only four
candidate drugs have been able to reach Phase III clinical trials
aimed at reversing the progression of NAFLD to steatohepatitis, and
subsequently to hepatocellular carcinoma (HCC) or cirrhosis, and all
failed to receive approval. The main reason for the failure of
candidate pharmaceuticals is the lack of robust and representative
human liver models to evaluate the effectiveness of candidate
molecules before advancing into clinical trials. The complexity of the
human liver niche challenges current available in vitro cultures as
predictive disease modeling platforms. This research proposal
provides a set of research objectives to better understand underlying
mechanism of the initiation and progression of steatohepatitis by
using human induced Pluripotent Stem Cell (hiPSC)-derived liver
progeny. The main target of the research proposal is to investigate
how crosstalk between hepatocytes and non-parenchymal cells are
evolved in response to lipotoxic induction. The knowledge generated
from this research will guide the development of new
pharmaceuticals by providing more accurate targets. The second aim
is to translate this knowledge for the development of real-time
imaging based in vitro platform to allow non-invasive assessment of
the efficacy of several Phase III pharmaceuticals.
condition with no approved pharmaceutical therapy. To date, only four
candidate drugs have been able to reach Phase III clinical trials
aimed at reversing the progression of NAFLD to steatohepatitis, and
subsequently to hepatocellular carcinoma (HCC) or cirrhosis, and all
failed to receive approval. The main reason for the failure of
candidate pharmaceuticals is the lack of robust and representative
human liver models to evaluate the effectiveness of candidate
molecules before advancing into clinical trials. The complexity of the
human liver niche challenges current available in vitro cultures as
predictive disease modeling platforms. This research proposal
provides a set of research objectives to better understand underlying
mechanism of the initiation and progression of steatohepatitis by
using human induced Pluripotent Stem Cell (hiPSC)-derived liver
progeny. The main target of the research proposal is to investigate
how crosstalk between hepatocytes and non-parenchymal cells are
evolved in response to lipotoxic induction. The knowledge generated
from this research will guide the development of new
pharmaceuticals by providing more accurate targets. The second aim
is to translate this knowledge for the development of real-time
imaging based in vitro platform to allow non-invasive assessment of
the efficacy of several Phase III pharmaceuticals.
Date:1 Oct 2022 → Today
Keywords:Liver Niche, Disease Modeling
Disciplines:Stem cell biology, Hepatology, Bioinformatics of disease, Cellular interactions and extracellular matrix