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On the Hemostatic Pathway in Stroke: An Integrated Clinical and Experimental Study

 

 

 

 

Fig. 1. The blood clot stops the blood supply to an area of brain leading to ischemia and eventual apoptosis.

 

 

 

Christina Jern

Contact InformationList of Publications

 

Stroke is both the second leading cause of death and a major cause of disability worldwide. Stroke also imposes a great socioeconomic burden. Despite this, there are many gaps of knowledge regarding risk factors, treatment and outcome.
Ischemia is the most common cause of stroke and blood clot formation is a key mechanistic event in ischemic stroke (Fig 1). Our group is therefore interested in understanding the role of hemostasis in ischemic stroke. 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 the hemostatic pathway is of importance for stroke incidence, stroke recurrence and/or post-stroke outcome, and to better understand the underlying molecular and genetic mechanisms associated with this pathway.

 

 

 

 

Fig. 2. The four most common etiologic subtypes of ischemic stroke

 

 

 

 

 

 

 

Clinical Studies
The cornerstone 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 controls. Even within the group of ischemic stroke, disease etiology shows heterogeneity (Fig 2). We are therefore studying the hemostatic pathway, both at the protein and genetic level, in the different subtypes of ischemic stroke. In collaboration with national and international partners, we are also studying stroke in other cohorts, and we participate in studies within the International Stroke Genetics Consortium (ISGC) and in a large multi-center genome wide association (GWA) study on ischemic stroke subtypes, the Stroke Genetics Network (SiGN) study. Our group also performs GWA studies on hemostatic protein levels.

Although stroke is traditionally associated with the elderly, recent studies show that stroke incidence is increasing in the young. While younger stroke patients have a low case-fatality, they face the risk of permanent disabilities and recurrent vascular events. We are therefore also performing a long-term prospective study of the participants in SAHLSIS with the aim of identifying biomarkers that predict outcome. 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.
(Click here for additional information about SAHLSIS)
(Click here for additional information about stroke and Stroke Centre West)

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 for FIND is similar to that used in SAHLSIS and involves in person assessments, postal questionnaires, and extraction of data from registers, with the important difference that we include patients at all ages referred to our stroke unit with a diagnosis stroke or transient ischemic attack (TIA) and we apply more frequent, 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 biomarkers in relation to the time course of recovery. 

 

Experimental Studies

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 identify cis-acting genetic variants and DNA methylation signatures involved in regulating hemostatic genes. Here we obtain fresh human liver tissue samples from the Dept. of Surgery at Sahlgrenska Hospital. We use a targeted approach to enrich and sequence selected genes (including introns, upstream and downstream regulatory regions) and mRNA transcripts. We utilize massively parallel gDNA-, mRNA- and bisulfite- sequencing to integrate high-resolution, quantitative, genetic, transcriptomic and epigenetic information for analysis of allele specific expression (ASE) and allele-specific DNA methylation (ASM). The strength of this approach is that by comparing expression of alleles within an individual, each allele acts as an internal control for confounding environmental and trans-acting effects. Therefore it is possible to map cis-acting variants using a low number of individuals. Variants found to alter gene expression/ DNA methylation will be tested for association to ischemic stroke, stroke subtype or outcomes.

Functional Characterization of Genetic Variants
Molecular genetic studies are used to investigate functional mechanisms underlying any observed associations from the clinical findings (techniques include cell culture, reporter gene assays, electrophoretic mobility shift assays, chromatin immunoprecipitation etc).

Group members

Christina Jern, MD, PhD, professor, group leader
Tara Stanne, PhD, researcher

Lukas Holmegaard, MD, PhD student
Annie Pedersen, MD, PhD student
Martina Olsson, MS, PhD student

Cecilia Lagging, MD, PhD student

Sofia Klasson, MSE


Ingrid Eriksson, research nurse

Susanne Nilsson, nurse
Sven-Öijvind Swahn, research engineer
 

 

Co-workers at the Institute of Neuroscience and Physiology
Katarina Jood, MD, PhD, group leader
Christian Blomstrand, MD, PhD, senior professor
 

Sidansvarig: Dan Baeckström|Sidan uppdaterades: 2018-10-04
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