Biography
Professor Robert A. Harris
Professor Robert A. Harris (Bob) was born in Harpenden in Southern UK in 1966. He conducted a Bsc.Hons undergraduate degree at Portsmouth Polytechnic, majoring in Parasitology in 1987. PhD studies at University College London studying innate immune agglutinins in Schistosoma host snail species with Terry Preston and Vaughan Southgate as supervisors culminated with a thesis defence in early 1991. A 2.5 year postdoc at the London School of Hygiene & Tropical Medicine in Paul Kaye’s research group ensued, with focus on understanding the intracellular fate of Leishmania spp. protozoans in macrophages. Bob was awarded a Wellcome Trust postdoctoral fellowship that permitted his relocation to the Karolinska Institutet (Stockholm, Sweden) in the spring of 1994. A postdoc period was spent split between the labs of Anders Örn and Tomas Olsson, in which he studied Trypanosoma cruzi and Trypanosoma bruceii protozoan proteins. Bob became an Associate Professor at the Karolinska Institutet in 1999, heralding his establishment as a PI. Bob started to work with autoimmune diseases in 1996 and began study of therapy using live parasite infections or parasite molecules. His research group has developed autoantigen-specific vaccines, defined the effects of post-translational biochemical molecules on autoantigenicity and developed a macrophage adoptive transfer therapy that prevents pathogenesis in several experimental disease models. He became Professor of Immunotherapy in Neurological Diseases in 2013. In recent years research focus has centred on understanding the immunopathogenesis of incurable neurodegenerative diseases, with particular emphasis on development of immunotherapies directed at microglial cells as potential therapeutic paradigms.
Bob Harris CV July 2020
ERIK HERLENIUS GROUP
Development of autonomic control
About
Immature or deficient autonomic control is a common problem in infants born at a premature age and is of central importance in apneas, secondary hypoxic brain damage and sudden infant death syndrome.
PER ERIKSSON GROUP
Research
For better understanding of disturbances in respiratory control we study early development of cardiorespiratory control, brainstem neural networks and its associations with normal and pathological breathing. The conceptual change introduced by our recent data that endogenous prostaglandins are central pathogenic factors in respiratory disorders and the hypoxic response, open new diagnostic and therapeutic avenues that should significantly better the diagnostics and treatment of newborns and adult patients.
Inflammation is a major culprit in breathing disorders and we hypothesize that by using a newly developed urinary prostaglandin biomarker we can screen, detect and protect against inflammation related breathing disorders.
Our collaborative efforts enable us to move from a clinical problem to molecular understanding of the disease and studies are performed in patients, animal & in vitro models.
Our research is focused on the development of autonomic control with normal and paediatric patients as the target. Autonomic dysfunction in breathing and circulatory control often has its origin in neurodevelopment disorders. Furthermore, our basic research in developmental neuroscience how neural activity and stem cells form activity dependent networks is vital for the development of therapeutic interventions.
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Contact: communication@cmm.se
CENTER FOR MOLECULAR MEDICINE
PER-JOHAN JAKOBSSON GROUP
Eicosanoids and Proteomics in Rheumatic Diseases
About
Rheumatoid arthritis (RA), rheumatic muscle inflammation (myositis) and systemic lupus erythomatosis (SLE) are all autoimmune diseases. This means that the immune defense has become self-reactive and instead of attacking foreign proteins is invading the body, the antibodies in our natural defense start to attack proteins within the body (with so called auto-antibodies). Little is known today about the origin of these autoantibodies and why they recognize certain parts of proteins in for example joints or muscles. The goal in our group is to identify these proteins and to characterize the process by which such self-proteins develop into targets of the immune system. We believe that neutralization of certain disease-specific autoantibodies may result in new therapeutic alternatives. In our group we have the capacity to generate big data of proteins and even parts of proteins in our search for autoantibody targets in patients with RA, myositis or SLE. We are also involved in the development of new anti-inflammatory drugs that are more powerful with lesser adverse effects for the patients, such as gastrointestinal or cardiovascular side-effects. Biological inhibitors against certain checkpoints in the synthesis of inflammatory molecules could be a more specific way of targeting inflammation compared to the commonly used non-steroidal anti-inflammatory drugs, i.e. aspirin.
Role of the induced PGE2 pathway in chronic inflammation
Microsomal prostaglandin E synthase (mPGES1) catalyzes the formation of prostaglandin (PG) E2 from cyclooxygenase derived PGH2. This enzyme is induced during inflammation and evidently linked to inflammatory conditions like joint inflammation (arthritis) and fever but also to other conditions such as stroke, cancer and breathing dysfunctions. A major goal in our group is to further characterize this enzyme on its molecular level as well as its role in diseases. In collaboration with NovaSAID we are also investigating inhibitors of mPGES1, which we believe can become a new generation anti-inflammatory drug with fewer side effects than traditional NSAIDs.
Prostaglandins belong to the family of eicosanoids which consists of fatty acid derived biologically potent metabolites. The two major pathways are the 5-lipoxygenase (5-LO) pathway, which produces leukotrienes and the cyclooxygenase (Cox) -1/2 pathway forming prostaglandins. The widely used non-steroidal anti-inflammatory drugs (NSAIDs) exert their actions by targeting Cox-1/Cox-2 with different specificities. There are several prostaglandins produced from Cox-derived PGH2 catalyzed by specific terminal PG synthases such as prostacyclin (PGI2), thromboxane (TxA2), PGF2a, PGE2 and PGD2. Through their respective receptors, these metabolites mediate biological effects like platelet aggregation (TxA2), vasodilation (PGI2) or inflammation (PGE2). There are three described enzymes that catalyze the formation of PGE2 from PGH2. Of these, only microsomal prostaglandin E synthase-1 (mPGES1) is inducible and studies using knock-out mice have shown that mPGES1 inhibition can be useful treating arthritis, fever, anorexia, atherosclerosis, stroke and cancer. Notably, unprovoked these mice are healthy [1].
In collaboration with NovaSAID AB, we are currently investigating the anti-inflammatory effects of mPGES1 inhibitors in various in vivo models of experimental arthritis as well as in relevant cellular in vitro systems. In patients, we have characterized the PGE2 pathway in rheumatoid arthritis and myositis and investigated the effect of anti-TNFa blockers or orally administrated corticosteroids on the expression of respective enzymes. Interestingly, the PGE2 pathway remains overexpressed in the synovial membrane and in muscles despite such treatments [2] [3] ,suggesting that PGE2 may still be formed and thus able to sustain inflammation. We are also studying the structure-function relationships of this enzyme and recently we described the 3D structure of mPGES1 [4]. We have now intensified our work characterizing the enzyme for better understanding of the mechanism of catalysis and to define substrates and inhibitors binding surfaces. This part of the project will provide useful information optimizing lead compounds and to understand their mechanisms of action.
Proteomics
We are also interested in studying rheumatic diseases by means of proteomics. We have recently described a quantitative mass-spectrometry based method allowing for relative quantification of both soluble and integral membrane proteins [5]. We are now aiming for defining antigens for autoantibodies in RA, myositis and SLE. Work is also in progress for identification of peptides bound to the major histocompatibility complex (HLA-D) isolated from antigen presenting cells in the affected joints. Characterization of autoantigens will provide better understanding of autoimmune diseases and may open for the development of new treatment options