Project Details
Projekt
The role of Hypoxia-inducible factor-1 dependent gene expression for pathogenesis of Graves Orbitopathy
Subject Area
Ophthalmology
Term
from 2013 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 244366632
Graves orbitopathy (GO) is an inflammatory eye disease which usually occurs in the context of Graves disease and it is believed that an autoimmune reaction against the Thyrotropin Receptor is the common cause. However, in the orbita, pathophysiological mechanisms for the development of GO are not understood. Graves orbitopathy is characterized by inflammation, remodeling, and expansion of the retroocular connective tissue. Because of the limited volume of the bony orbita, these changes can lead to proptosis, extraocular muscle dysfunction, and, in severe cases, optic nerve compression. Orbital fibroblasts (OFs) represent the most abundant cell type in the orbital tissue and are the central cell type for inflammation and tissue remodelling in GO. Once activated during the inflammatory process OFs react with excessive proliferation and adipogenesis, as well as exaggerated production of hydrophilic hyaluronic acid and proinflammatory cytokines. Changes in and expansion of the OF compartment are an essential element in the mass-to-volume mismatch typical of GO. However, the expansion of the orbital tissue within the confined space of the orbita may cause a strong hypoxic microenvironment. Cells generally respond to hypoxia mainly by adapting gene expression through the activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). The detection of its oxygen labile HIF-1alpha subunit and subsequent HIF-1 activity are understood to be independent, prognostic factors in many inflammatory malignancies. Indeed we found HIF-1alpha positive fibroblast-like cells in the orbital fat tissue of GO patients but almost not in fat tissue of healthy control persons. In accordance to that, OFs derived from GO patients expressed more HIF-1alpha than control OFs even under normoxia. In response to hypoxia the HIF-1alpha levels were strongly induced and correlated positively with the clinical activity score of the eye disease. Thyroid hormone and insulin like growth factor-1 enhanced HIF-1alpha expression in addition. Consequently, GO-OFs exhibited more HIF-1 activity leading to changes in the expression of metabolic, proangiogenic and adipogenic genes.Our findings strongly suggest that HIF-1 dependent gene expression is involved in different processes leading to the complex pathophysiology of GO. Our aim is to further elucidate the role of HIF-1 dependent gene expression and signaling as an underlying mechanism that promote or delay the progression of the eye disease and could define the potential outcome for patients. Therefore we aim (A) to understand the mechanisms maintaining the pre-stimulation of the GO-OFs with respect to HIF-1alpha expression, (B) to investigate the impact of HIF-1 dependent signaling for autocrine activation of GO-OFs and (C) the consequences of HIF-1 activity for adipogenesis and inflammatory response in the orbita.
DFG Programme
Research Grants
