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On prothrombotic pathways and blood biomarkers in ischemic stroke: an integrated clinical and experimental study

Research group
Active research
Project owner
Institute of Biomedicine

Short description

Stroke is the second most common cause of death and the most common cause of disability in adults. The most common type of stroke is so-called ischemic stroke, which occurs due to a blood clot in one of the brain’s vessels. The project focuses on increasing the knowledge of underlying mechanisms in ischemic stroke and on factors of importance for post-stroke recovery. We study so-called biomarkers and genetic factors. The long-term goal is to contribute to the development of precision medicine in stroke, i.e. more individualized treatments and interventions in stroke.

Worldwide one in four people will experience a stroke during their lifetime. Stroke is the second most common cause of death and the foremost cause of adult disability. Stroke also imposes a great societal and economic burden. Despite this, there are many gaps of knowledge regarding risk factors, treatment and outcome.
 

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Blood clot formation
Fig. 1

The causes of stroke are ischemia or bleeding, with ischemia accounting for the majority of cases. Blood clot formation is a key mechanistic event in ischemic stroke (Fig 1), therefore this project focuses on the prothrombotic pathway. As the molecular underpinnings leading to ischemic stroke are largely unclear, we complement these targeted studies with broader blood biomarker studies that provide an opportunity to identify novel pathways involved in ischemic stroke pathophysiology. Our research includes both clinical and experimental methodologies and uses a “bi-directional” translational approach; that is to say that findings from our clinical studies are investigated further in the laboratory and vice versa. The main overall aim is to test the hypothesis that prothrombotic pathways are of importance for stroke incidence, stroke recurrence and/or post-stroke outcomes, and to better understand the underlying genetics and molecular mechanisms. In the future, the knowledge gained from this project may suggest novel targets for therapy and lay the foundation for individual risk profiling and secondary prevention of ischemic stroke.

 

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Ischemic stroke etiology shows heterogeneity
Fig. 2

Clinical Studies

The Sahlgrenska Academy Study on Ischemic Stroke 
One of the cornerstones for our project is the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), a cohort of patients with ischemic stroke before 70 years of age and population based controls. Even within the group of ischemic stroke, disease etiology shows heterogeneity (Fig 2). We seek subtype-specific blood biomarker profiles (e.g. protein, RNA and genetic) using two complementary approaches: hypothesis-based (i.e. prothrombotic pathways) and hypothesis-generating (i.e. multiomic profiling). Genetic studies are performed in collaboration with national and international partners.  We are actively engaged in the International Stroke Genetics Consortium (ISGC) and participate in several large multi-center genome wide association studies (GWAS) on stroke. Our group also leads a GWAS on ischemic stroke outcome (the Genetics of Ischemic Stroke Functional Outcome (GISCOME) study).

Long-term outcomes after ischemic stroke at young age
Although stroke is traditionally associated with the elderly, the overall burden of stroke in adults below 70 years of age now represents almost half of the total burden from stroke. Yet, surprisingly little is known about long-term outcomes for this age group. We are therefore performing a long-term follow-up study of the participants in SAHLSIS with the aim of identifying blood-biomarkers that predict outcomes such as neurological and cognitive impairments. 

FIND Stroke Recovery 
Data on the time course of recovery and biomarkers after stroke are very scarce, and thus we are also performing a prospective longitudinal study, “FIND Stroke Recovery: a longitudinal frequent evaluation long-term follow-up study “. The protocol includes repeated measurements of outcomes to allow for objective measurements of changes in impairments in different domains over time. We also biobank samples at these set time points to enable evaluation of the time course of blood biomarkers in relation to the time course of recovery.

 

Experimental Studies

The Liver Project
As this project focuses on the prothrombotic pathway, it includes experimental studies of mechanisms regulating prothrombotic gene expression. Altered expression of genes involved in hemostasis can shift the balance towards thrombosis or bleeding, and thereby increase the risk for thrombotic or bleeding events. Many hemostatic proteins are produced in the liver and gene regulation can be tissue-specific. We therefore initiated The Liver Project with the aim to better understand the mechanisms involved in regulating hemostatic gene expression. For this project we obtained fresh human liver tissue and blood samples from the Dept. of Surgery at the Sahlgrenska University Hospital. We integrate various kinds of data to understand how genetic variation and DNA methylation influence overall gene expression and alternative splicing (alternative mRNA isoforms). Variants that alter gene expression, DNA methylation or are involved in alternative splicing are then tested for association to ischemic stroke, stroke subtype and/or outcomes.

Functional Characterization of Genetic Variants
We interrogate in silico datasets to characterize the regulatory potential of genetic variants identified through the studies described above. Variants exhibiting the most promising regulatory potential are taken forward for functional characterization in the lab. 

The group leader is engaged in several outreach activities regarding stroke, and is Chairman of the Steering Committee of Stroke Centrum Väst (SCV) and Fellow of the European Stroke Organisation (FESO).

 

Christina Jern

Group members

Tara Stanne, PhD, researcher

Annie Pedersen, MD, PhD

Cecilia Brännmark, MD student, PhD

Lukas Holmegaard, MD, engineer, PhD student

Cecilia Lagging, MD, PhD student

Annelie Angerfors, engineer, PhD student

Sofia Klasson, research engineer

Malin Johansson, MSc

Robert Månsby, MD student

Björn Andersson, PhD, statistician

Susanne Nilsson, nurse

Co-workers at the Institute of Neuroscience and Physiology

Katarina Jood, MD, PhD, group leader

Christian Blomstrand, MD, PhD, senior professor