Defining the role of Factor Inhibiting HIF (FIH) as a key regulator of extracellular matrix homeostasis

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The extracellular matrix (ECM) is one of the most important regulators of cellular and tissue function in the body. Dynamic remodeling of ECM is essential for development, wound healing and normal organ homeostasis. Life-threatening pathological conditions, such as organ fibrosis, arise when ECM remodeling becomes excessive or uncontrolled. The ECM is defined as the diverse collection of proteins and sugars that surrounds cells in all solid tissues. Although the ECM has historically been perceived as fulfilling a primarily structural and hence biomechanical role, the ability of the ECM to provide the contextual information responsible for controlling both individual and collective cellular behavior has been increasingly recognized in recent years. The biomechanical properties of the ECM are tightly controlled by the specific composition and concentration of matrix components, and also by post-translational modifications, such as glycosylation, transglutamination and cross-linking. We have recently identified that fibrotic lung tissue is stiffer than normal due to increased 'bone' type collagen cross-linking and that this promotes fibrosis progression. Through human in vitro and tissue analyses we identified that HIF pathway activation drives this pathologic 'bone type' crosslinking, and that this is determined through oxygen-independent activation of HIF signalling - termed pseudohypoxia - by loss of activity of Factor Inhibiting HIF (FIH). Furthermore, we identified that a high HIF gene signature score is strongly predictive of mortality of lung fibrosis independent of lung physiology severity. Thus, our hypothesis is that loss of function of FIH creates a pseudohypoxic phenotype that drives progressive fibrosis. The aims of this project are to use advanced primary human cell and tissue based models complemented by systems and quantitative biology approaches to determine:(1) global transcriptomic profiling of FIH-depleted lung fibroblasts;(2) biological and molecular changes following FIH depletion in lung fibroblast;(3) the impact of loss of FIH activity on ECM homeostasis.This project will define the role of FIH as a key regulator of extracellular matrix remodelling.