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.
Read more
Contact: communication@cmm.se
CENTER FOR MOLECULAR MEDICINE
JOHN PERNOW GROUP
Cardiology
About
The role of endothelial and red blood cell dysfunction in coronary artery disease and myocardial ischemia-reperfusion injury.
Our research is focused on 1) the identification of disease mechanisms and 2) development of novel therapeutic strategies to improve endothelial function in coronary artery disease (CAD) and limit the extent of myocardial infarction. Occurrence of endothelial dysfunction characterized by reduced availability of nitric oxide (NO) is an early factor during development of CAD and tissue injury during ischemia-reperfusion. This is of particular importance in diabetes which considerably increases the risk for CAD. We have identified key regulators of NO including the enzyme arginase that is upregulated in CAD and diabetes and reciprocally regulates NO formation and oxidative stress. Targeting arginase improves endothelial function and protects against myocardial ischemia-reperfusion injury. Our recent data suggest an intriguing role of red blood cell arginase as a critical regulator of NO production and reactive oxygen species both in red blood cells and the vasculature. Future projects will test the hypothesis that inhibition of arginase in the vasculature and red blood cells improves cardiovascular function in CAD and risk factors associated with CAD including diabetes and hypercholesterolemia. Further, we investigate the mechanisms behind and the therapeutic effects of remote ischemic perconditioning (RIPC) i.e. the signalling of cardiac protective effect by brief periods of remote ischemia.
Aims
The overall aim is to identify the key mechanisms regulating the bioavailability of NO in the development of CAD and myocardial ischemia-reperfusion injury. The importance of these mechanisms as therapeutic targets is tested in early interventional studies using disease animal models and clinical cohorts. The following specific objectives are set to be achieved:
1. To evaluate the role of arginase as a regulator of NO bioavailability and in endothelial and red blood cells.
2. To explore the functional importance of endothelial and red blood cell arginase/NO for vascular function and myocardial ischemia-reperfusion in experimental animals and patients with CAD risk factors.
3. To clarify the mechanisms behind and the therapeutic effect of RIPC in myocardial ischemia-reperfusion injury.
Methods and work plan
Experimental studies are performed on isolated heart preparations and in vivo models of myocardial ischemia-reperfusion using control and diabetic rat and mouse models. Isolated hearts are used for detail investigations of red blood cell biology. The therapeutic effect of arginase inhibition is investigated by evaluation of endothelial function in patients with CAD, diabetes and hypercholesterolemia. Molecular signalling and the therapeutic effect of RIPC is investigated in experimental and clinical studies on patients with ST-elevation myocardial infarction.
Significance
The project will provide novel insights into molecular mechanisms driving development of CAD and myocardial ischemia-reperfusion injury. Targets identified in experimental studies are tested in early clinical interventional studies that will provide the basis for novel therapeutic strategies.
Selected publications
Cortese-Krott MM, Mergia E, Kramer CM, Lückstädt W, Yang J, Wolff G, Panknin C, Bracht T, Sitek B, Pernow J, Stasch JP, Feelisch M, Koesling D, Kelm M. Identification of a soluble guanylate cyclase in RBCs: preserved activity in patients with coronary artery disease. Redox Biol. 2018 Apr;14:328-337.
Basalay MV, Mastitskaya S, Mrochek A, Ackland GL, Del Arroyo AG, Sanchez J, Sjoquist PO, Pernow J, Gourine AV, Gourine A. Glucagon-like peptide-1 (GLP-1) mediates cardioprotection by remote ischaemic conditioning. Cardiovasc Res. 2016 Dec;112(3):669-676.
Kiss A, Tratsiakovich Y, Mahdi A, Yang J, Gonon AT, Podesser BK, Pernow J. Vagal nerve stimulation reduces infarct size via a mechanism involving the alpha-7 nicotinic acetylcholine receptor and down-regulation of cardiac and vascular arginase. Acta Physiol (Oxf). 2017 Nov;221(3):174-181.
Kövamees O, Shemyakin A, Checa A, Wheelock CE, Lundberg JO, Östenson C-G, Pernow J. Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes mellitus. J Clin Endocrin Met. 2016 Nov;101(11):3952-3958..
Verouhis D, Sörensson P, Gourine A, Henareh L, Persson J, Saleh N, Settergren M, Sundqvist M, Tornvall P, Witt N, Böhm F, Pernow J. Effect of remote ischemic conditioning on infarct size in patients with anterior ST-elevation myocardial infarction. Am Heart J.2016 Nov;181:66-73.
Kövamees O, Shemyakin A, Eriksson M, Angelin B, Pernow J. Arginase inhibition improves endothelial function in patients with familial hypercholesterolaemia irrespective of their cholesterol levels. J Intern Med. 2016 May;279(5):477-84.4.
Kiss A, Tratsiakovich Y, Gonon AT, Fedotovskaya O, Lanner JT, Andersson DC, Yang J, Pernow J. The role of arginase and rho kinase in cardioprotection from remote ischemic perconditioning in non-diabetic and diabetic rat in vivo. PLoS One 2014 Aug 20;9(8):e104731.
Kövamees O, Shemyakin A, Pernow J. Effect of arginase inhibition on ischemia-reperfusion injury in patients with coronary artery disease with and without diabetes mellitus. PLoS One. 2014 Jul 29;9:e103260.
Yang J, Gonon AT, Sjöquist PO, Lundberg JON, Pernow J. Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15049-54.
Shemyakin A, Kövamees O, Rafnsson A, Böhm F, Svenarud P, Settergren M, Jung C, Pernow J. Arginase inhibition improves endothelial function in patients with coronary artery disease and type 2 diabetes mellitus. Circulation. 2012 Dec 18;126(25):2943-50.
Ammirati E, et al. Identification and Predictive Value of IL6(+)IL10(+) and IL6(-)IL10(+) Cytokine Patterns in ST-Elevation Acute Myocardial Infarction. Circ Res. 2012 Oct 26;111:1336-48.
Rafnsson A, Böhm F, Settergren M, Gonon A, Brismar K, Pernow J. The endothelin receptor antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes mellitus and microalbuminuria: a randomised trial. Diabetologia. 2012 Mar;55(3):600-7.
Shemyakin A, Salehzadeh F, Esteves Duque-Guimaraes D, Böhm F, Rullman E, Gustafsson T, Pernow J, Krook A. Endothelin-1 reduces glucose uptake in human skeletal muscle in vivo and in vitro. Diabetes. 2011 Aug;60(8):2061-7.
Grönros J, Jung C, Lundberg JON, Östenson C-G, Pernow J. Arginase Inhibition Restores in vivo Coronary Microvascular Function in Type 2 Diabetic Rats. Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1174-81.
Sörensson P, Saleh N, Bouvier F, Böhm F, Settergren M, Caidahl K, Tornvall P, Arheden H, Rydèn L, Pernow J. Effect of postconditioning on myocardial infarct size in patients with ST-elevation myocardial infarction. Heart. 2010 Nov;96(21):1710-5.
Jung C, Gonon AT, Sjöquist PO, Lundberg JO, Pernow J. Arginase inhibition mediates cardioprotection during ischaemia-reperfusion. Cardiovasc Res. 2010 Jan 1;85(1):147-54.