Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

KI News

Updated: 28 min 59 sec ago

New immunological findings provide possible therapy for cardiovascular disease

Fri, 14/11/2014 - 08:08
A new immunological mechanism in atherosclerosis and cardiovascular disease has been presented in a study from Karolinska Institutet in Sweden. The study is being published in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, and also indicates a possible treatment method for these diseases. Atherosclerosis is an inflammatory process where lipidsin the form of LDL cholesterol (‘bad cholesterol’) are stored in the artery walls. The activation of the immune system in the form of T-cells, among others, plays a vital role, particularly for rupturing the atherosclerotic plaques which, the primary cause of myocardial infarction and stroke. LDL is only taken up in the artery wall after modification, a process where oxidation is one probable underlying cause. Enzymes in the artery walls can also modify LDL making it inflammatory. Most basic scientific studies in the field are based mouse models with genetic changes as mice cannot develop arteriosclerosis or cardiovascular disease. Plaque cells and blood Together with his research team, Dr. Johan Frostegård, Professor of Medicine at the Institute of Environmental Medicine at Karolinska Institutet, has studied inflammatory and immune defence reactions in atherosclerosis and cardiovascular disease using plaque cells and blood from patients with cardiovascular disease. The researchers have observed that the lipids (phospholipids) in modified LDL appear to be one of the primary causes. The research team has shown that LDL that is modified by enzymes in the artery walls can activate dendritic cells, which in turn play a key role in activating the T-cells. Non-modified, regular LDL on the other hand had no effect on these cells in the study. The research also indicates the possible existence of a mechanism, namely that stress proteins (also called heat shock proteins) are expressed, which is decisive when modified LDL activates the dendritic cells and T-cells. The study shows that a plasma protein Annexin A5 decreases inflammation and modulates immune reactions to modified LDL, which creates a protective effect. “Studying the inflammatory process and immune reactions directly in cells from people with cardiovascular disease is a unique opportunity to discover the causes and new mechanisms behind the disease's progression. We have shown that modified LDL can play a key role and that stress proteins have a major significance to immune defence reaction,” says Johan Frostegård. Fighting inflammatory process With the new results, Dr. Frostegård and his team hope to find a strategy for fighting the inflammatory process. “We have shown that Annexin 5 is a possible new therapy for fighting inflammation and supports the immune defence system is a positive way. We hope to develop this protein into a new type of anti-inflammatory treatment for atherosclerotic disease,” he says. The study was funded with grants from the Torsten Söderberg Foundation, Vinnova, the EU, and RMR. Johan Frostegård is also specialist consultant at the Emergency Clinic at Karolinska University Hospital, Huddinge in Stockholm County. The researchers and their European partners have applied for a larger EU grant to fund the continuing basic research studies and also treatment studies on patients with cardiovascular disease, which is backed by several patents. View a press release about the findings Publication Induction of dendritic cell-mediated T cell activation by modified but not native LDL in humans and inhibition by Annexin A5: involvement of heat shock proteins Liu A, Ming J, Fiskesund R, Ninio E, Karabina S, Bergmark C, Frostegård AG, Frostegård J Arteriosclerosis, Thrombosis, and Vascular Biology, published online before print November 13, 2014,doi: 10.1161/ATVBAHA.114.304342  

Molecular time signalling controls stem cells during brain development

Thu, 13/11/2014 - 18:18
Researchers at Karolinska Institutet have succeeded in explaining how stem cells in the brain change to allow one type of stem cell to produce different cell types at different stages. In a study being published in the journal Neuron, researchers show that the signal molecule TGF-beta acts as a time signal that regulates the nerve stem cells' potential at different stages of the brain's development – knowledge that may be significant for future pharmaceutical development. The human brain consists of thousands of different types of nerve cells that are all formed out of what in simple terms can be described as immature stem cells. It has long been known that the neural stem cells change as the human brain develops and ages. One type of stem cell can produce multiple types of nerve cells at different stages of the brain's development. In this process, ageing stem cells also gradually become more limited in their development potential and lose the ability to develop the maturated cell types that form during the early stages. How neural stem cell identity and potential is regulated over time has been poorly understood. But in the study being published, researchers at the Department of Cell and Molecular Biology at Karolinska Institutet present a molecular time mechanism that can help explain neuronal stem cell regulation and therefore also the occurrence of cellular diversity in the brain. “TGF-beta functions as an important time signal that controls when a stem cell should stop producing one type of nerve cell and instead start producing another, while also gradually limiting the stem cell's  future development capacity,” says Johan Ericson, Professor of Developmental Biology, who led the study. Mass-prduction of nerve cells In their work, the researchers also show how TGF-beta can be used in stem cell cultures to mass-produce nerve cells which in turn produce the signalling substance serotonin. Today the brain's serotonin system is already a known target for the treatment of depression, and according to researchers it should be possible to use time signals in pharmaceutical development based on stem cells. “This is the first known signalling molecule that regulates the potential of neuronal stem cells”, says Johan Ericson. “With a better understanding of how potential is regulated, it could be possible to broaden the development spectrum of ageing stem cells, allowing them to regain their capacity to produce cell types from earlier development stages, which in the long-term perspective could be relevant to future treatment methods for neurodegenerative disease”. The research was funded by grants from the Swedish Foundation for Strategic Research (SSF), Knut and Alice Wallenberg Foundation, Swedish Research Council, Swedish Cancer Society and Swedish Brain Foundation. View a press release about this research Publication Tgfβ signaling regulates temporal neurogenesis and potency of neural stem cells in the CNS  José M. Dias, Zhanna Alekseenko, Joanna M. Applequist and Johan Ericson Neuron, online 13 November 2014, DOI: http://dx.doi.org/10.1016/j.neuron.2014.10.033

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