Inflammation and functional studies of novel gene variants in the pathogenesis of venous thromboembolism
inflammation by mechanisms implicated in most inflammatory-induced diseases.
In particular complement and specific Toll-like receptors are known to play an important role in the initiation and progression of atherosclerosis, and experimental and clinical data provide evidence for a strong interplay between inflammation/complement and coagulation in different disease states.
Several plasma coagulation factor levels (e.g. FXI, FIX and FVIII) have been related to venous thromboembolism risk, but the case-control design of these studies makes it impossible to conclude whether the risk of venous thromboembolism by coagulation factor levels is causal, or merely a consequence of the disease (reverse causation).
Accordingly, little is known about the role of coagulation, complement and inflammation, and their interplay in the pathogenesis of venous thromboembolism.
It is expected that we will identify novel gene variants of soluble proteins that may be part of or interact with the coagulation and complement systems, both parts of the inflammation network, that are associated with venous thromboembolism risk. Plasma levels of these proteins, which are also affected by environmental conditions, are expected to enhance the risk of venous thromboembolism (gene-phenotype interactions).
We will conduct a nested case-control study to determine if single protein levels are associated with risk of venous thromboembolism and explore how pathway interactions affect risk of venous thromboembolism.
Likewise, we also expect to identify gene variants in cell-specific receptors or intracellular molecules that may modify cellular behavior to promote thrombosis. We will functionally characterize common and rare gene variants in cell-specific receptors and intracellular molecules with respect to the pathogenesis of venous thromboembolism by using site-directed mutagenesis combined with endogenous protein knock-down in experimental systems.
Last updated: 28.04.2019 12:03