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On the Hemostatic and Inflammatory Pathways in Ischemic Stroke: An Integrated Clinical and Experimental Study

Research group
Pågående forskning
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 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 that are important for post-stroke recovery. We study biomarkers, mainly protein levels in blood and genetic factors. The long-term goal is to contribute to the development of precision medicine in stroke, i.e. more individualized treatments and other interventions.

Worldwide one in six 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.
 

Image
Blood clot formation
Fig. 1

The main causes of stroke are ischemia and bleeding, with ischemia accounting for the majority of cases. Blood clot formation is a key mechanistic event in ischemic stroke (Fig 1), and inflammation is involved in many underlying pathophysiological processes. Therefore, this project focuses on the hemostatic and inflammatory pathways in ischemic stroke. We complement these more focused studies with broad proteomics and genome-wide genetic studies that provide an opportunity to identify novel pathways involved in stroke pathology and outcomes. Our research includes both clinical and experimental methodologies and uses a “bi-directional” translational approach; i.e. findings from our clinical studies are investigated further in the laboratory and vice versa. The main overall aim is to test the hypothesis that the hemostatic and inflammatory pathways are of importance for stroke incidence, stroke recurrence and/or post-stroke outcomes, and to better understand the underlying molecular and genetic mechanisms.

Image
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 are therefore studying the hemostatic and inflammatory pathways, both at the protein and genetic level, in different subtypes of ischemic stroke. We investigate whether certain pathways are shared by all main subtypes, whereas others are subtype-specific. In collaboration with national and international partners, we are also studying stroke subtypes in other cohorts.  We are actively engaged in the International Stroke Genetics Consortium (ISGC) and in several large multi-center genome wide association studies (GWAS) on stroke such as MEGASTROKE and the Stroke Genetics Network (SiGN) study. 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 younger adults 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 youngest group of participants in SAHLSIS with the aim of identifying biomarkers that predict outcomes such as neurological and cognitive impairments. 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.

FIND Stroke Recovery

Data on the time course of recovery and biomarkers after stroke are very scarce, and thus we recently initiated a new 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

Most hemostatic proteins are produced in the liver. The mechanisms regulating the synthesis and release of these factors are crucial for a functional hemostatic system and to avoid thrombus formation. We therefore initiated “The Liver Project” with the aim to better understand how genes involved in hemostasis are regulated. For this project we obtained fresh human liver tissue and blood samples from the Dept. of Surgery at the Sahlgrenska University Hospital. We designed a targeted approach to enrich and sequence 35 carefully selected genes (including introns, upstream and downstream regulatory regions) and mRNA transcripts encoding proteins that are important for hemostasis. We utilize massively parallel gDNA-, mRNA- and bisulfite- sequencing to integrate high-resolution, quantitative, genetic, transcriptomic and epigenetic information. This integrative approach with different types of data, using state-of-the-art technologies is combined with advanced bioinformatics tools, which enables the identification of novel genetic variants and DNA methylation signatures that are correlated to mRNA expression in the human liver, and provides insights into the mechanisms involved in regulating genes involved in hemostasis. Variants that alter gene expression/ DNA methylation are 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

Annie Pedersen

Lukas Holmegaard

Cecilia Lagging

Annelie Angerfors

Sofia Klasson

Malin Johansson

Björn Andersson

Ingrid Eriksson

Susanne Nilsson

Co-workers at the Institute of Neuroscience and Physiology

Katarina Jood, group leader

Christian Blomstrand