Research projects

Novel treatment options for inherited coagulation factor (F) VII deficiency

Coagulation FVII is produced in the liver and secreted to the blood stream where it circulates as an inactive zymogen. In the event of vascular damage, FVII is activated and fuels the coagulation cascade that is essential for proper clot formation in order to stop the bleeding. Inherited FVII deficiency is caused by mutations in the F7 gene leading to reduced FVII antigen and/or activity levels in the blood and potentially severe bleeding symptoms in the patient. Although the disease is rare, it is the most common of the inherited coagulation factor deficiencies and has a 10-fold higher prevalence in Norway. Factor replacement therapy is the only available treatment for these patients, however, it is not optimal due to a short half-life and high cost. To explore new potential therapeutic approaches that can substitute the present replacement therapy, we are investigating the intracellular fate of different FVII proteins containing mutations previously reported to cause FVII deficiency and bleeding symptoms. The studies are done in physiological relevant liver cell models that express mutated FVII protein, which are generated by genomic editing of immortalized human pluripotent stem cells differentiated into hepatocyte-like cells. Our goal is to use genome editing to correct the FVII mutation in patients-derived cells and to find chemical/pharmacological compounds that can improve the secretion of an active FVII.

Coagulation factor (F) V and TFPI in atherosclerotic inflammation

A bi-directional relationship between blood coagulation and inflammation has existed for millions of years, and it is clinically evident even today as patients with chronic inflammatory diseases are at higher risk of thrombosis. Atherosclerosis is now recognized as an inflammatory driven disease, where accumulation of immune cells together with lipids causes the artery wall to expand into the vessel lumen, restricting blood flow. Occasionally, these plaques rupture, breaking the protective endothelial lining in the vessel and resulting in thrombus formation, which is the main cause of myocardial infarction and stroke. Using a biobank of human carotid plaques, we are investigating the presence of coagulation factors inside the plaque, and their role in regulating inflammation in the plaque and thus atherosclerotic development. The aim is to identify potential new therapeutic targets that can reduce the inflammatory burden and, potentially, be beneficial in attenuating atherothrombosis.

TFPI and migration of leukemia cells

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Cell trafficking and homing of CLL cells play a critical role in organ infiltration and contribute to the clinical course of CLL. Interaction between CLL cells and endothelial cells affects gene expression in CLL cells and further regulates cell trafficking. Endothelial cells are the main source of tissue factor (TF) pathway inhibitor (TFPI), which is the primary inhibitor of TF. Research showed that TFPI is involved in cell migration in solid tumor. However, the role of TFPI in the progression of solid tumors is still controversial and the effect of TFPI on leukemia progression has not been investigated. In an attempt to find new therapeutic approaches to CLL organ infiltration, we are studying the role of TFPI in the migration of aberrant B cells from patients with CLL.

TFPI-2 regulation by microRNAs

Although TFPI-2 is structurally similar to TFPI, it has a different, non-hemostatic function and is considered a tumor suppressor involved in regulating tumor progression, invasion and metastasis in breast cancer cells. Clinically, TFPI-2 expression is positively correlated to the survival of breast cancer patients, and thus the molecular mechanism behind the regulation of TFPI-2 expression is of great interest. Micro-RNAs (miRNAs) have been increasingly Using the GOBO database, we found that the TFPI-2 mRNA levels were significantly increased in patients with ERα+ tumors compared to patients with ERα- tumors and that increased levels of TFPI-2 were associated with increased survival in patients with ERα+ tumors. We have demonstrated that estrogens induced TFPI-2 expression in ER positive breast cancer cells in a process mediated by ERα and a specific lysine demethylase.  A continuation of this project is in progress where potential effects on TFPI-2 expression by miR-RNAs are being examined.

TFPI regulation by transcription factor FOXP3

Previously, we have seen that the -287T/C single nucleotide polymorphism (SNP) of the tissue factor pathway inhibitor (TFPI) gene promoter region exerts differential impact on TFPI mRNA expression, with the C allele being associated with higher TFPI expression than the T allele. Increased expression of TFPI is in turn associated with reduced risk of thrombosis, and the SNP may therefore play an important role in the occurrence of thrombosis in the carriers. In the current project, we aimed to reveal the underlying molecular mechanisms of the differential gene regulation of TFPI caused by the SNP. Using bioinformatics, three potential candidate transcription factors for binding to the two -287 alleles were predicted, of which one, FOXP3, showed increased binding to the T allele compared to the C allele in various analyses. Furthermore, knock down or overexpression of FOXP3 resulted in increased or decreased TFPI levels, respectively, showing a repressor function of FOXP3. In conclusion, this study indicated that FOXP3, a transcription factor initially identified as a functional marker of T regulatory cells, may be the underlying cause to the increased levels of TFPI observed with the -287C allele.

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