Download Exploring the Role of Fibroblast Growth Factor Receptor Signaling in Liver Fibrosis

NUS Graduate School for Integrative Sciences and Engineering
Research Project Write-up
Title of Project :
Exploring the role of fibroblast growth factor receptor
Name of Supervisor :
Dr. Ho Han Kiat
Contact Details:
[email protected]
Short Description
Introduction
Liver fibrosis is an intrinsic response to liver injury arising from different
etiologies such as viral hepatitis, alcoholic injury and drug-induced damage.
However, when fibrosis progresses into a longer term effect, it can aggravate
into cirrhosis or even cancer. Cirrhosis is an end state manifestation of such
pathological fibrosis, and itself is the single most important predictor of
hepatocellular carcinoma (HCC), where majority of HCC arise from the
background of liver cirrhosis as a pre-neoplastic event. Given that HCC is the
3rd largest cause of cancer deaths worldwide, and the frequent occurrence of
fibrosis from various causes, it is conceivable that overcoming cirrhosis would
have immense benefit on the overall healthcare, particularly in Asia where
HCC is prevalent.
Hepatic stellate cells (HSC) is the main fibroblast in the liver that when
activated, deposits collagen to yield a fibrotic phenotype. Hence, arresting key
signalling processes in HSC is considered as a viable option to inhibit this
pathological progression. To date, tyrosine kinases like VEGFR and PDGFR
have been linked to its activity and small inhibitors like sorafenib and sunitinib
have found some success as potential agents with anti-fibrotic action. This
early breakthrough raised a broader question of what might be other signalling
pathways in HSC that drives fibrogenesis that are amenable for inhibition as a
drug target. This speculation led us to our hypothesis that FGFR-mediated
signalling may have a significant impact to be considered as a new drug
target.
Fibroblast growth factor receptor includes FGFR1-4. As a family, they play
key role in wound healing, cell proliferation, angiogenesis and embryogenesis.
Expectedly, dysregulation in their signalling have led to pathologies such as
malignancies as well as growth disorders. Specific to the context of this
proposal, these receptors are activated by the binding of fibroblast growth
factors as ligands, as these are key drivers for fibrogenic behaviour of various
cell types, most notably fibroblasts. A recent application in terms of using
FGFR inhibitor for the pulmonary fibrosis further created a potential
consideration of an equivalent effect in liver fibrosis. Therefore, these
postulations await an objective and comprehensive investigation to provide
direct evidence for their role in HSC-mediated liver fibrosis to support further
development.
Hypotheses/research question
Given the current threshold of information, we hypothesize that FGFRs have
key role in the regulation of HSC-mediated fibrogenesis in the liver. The ability
to alter their activity would modulate this function as a potential strategy to
limit pathological fibrosis and subsequent liver cirrhosis. Furthermore, since
there are 4 distinct receptors in the FGFR family, we postulate that each
member may participate differentially in this process. Thus, identifying the key
contributor to HSC activity would help conjure a response that is
therapeutically advantageous.
Approach
With this goal in mind, we set out to approach the problem using 3 broad
strokes of experimental platforms:
1. To establish mechanistic insights to the action of FGFR signaling on
HSC activation using in vitro cell culture model
2. Kinase profiling of cirrhotic patient-derived hepatic stellate cells
3. Animal models of cirrhosis and testing of potential anti-fibrotic
agents