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NOX enzymes and redox regulation in the central nervous system: studies using genetically modified rodents and pluripotent stem cells

English title NOX enzymes and redox regulation in the central nervous system: studies using genetically modified rodents and pluripotent stem cells
Applicant Krause Karl-Heinz
Number 125115
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Pathophysiology
Start/End 01.04.2009 - 31.03.2012
Approved amount 840'000.00
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Keywords (12)

NOX; CNS; rodent; pluripotent stem cell; Reactive oxygen species; oxidative stress; central nervous system; knock-out mice; neuronal differentiation; NMDA receptor; hypertension; psychosocial stress

Lay Summary (English)

Lead
Lay summary
NADPH oxidases of the NOX family are a group of enzymes that are specialized in the generation of reactive oxygen species, ROS (often also refered to as oxygen radicals). Previously, ROS were considered as destructive entities, exclusively linked to aging and disease. Research over the last decade has proven this concept wrong. Generation of ROS at low levels is a physiologically important process, and only deregulated generation of ROS leads to disease. In our research project we propose to study the role of ROS-generating NADPH oxidases in physiological and pathophysiological events in the brain. Concerning physiology, we are particularly interested in ROS during neurodevelopment and in processes related to learning. Concerning pathologies, we are particularly interested in psychosis and brain aspects of hypertension. Our results should provide a novel understanding of how ROS are physiologically important if produced at the right moment and the right place, but lead to damage if deregulation occurs. This should have an important impact on our understanding of this hitherto little known aspects of brain function. It might also have long-term implications in terms of brain imaging and treatment of diseases of the central nervous system.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
NOX5: from basic biology to signaling and disease
Bedard K, Jaquet V, Krause KH (2012), NOX5: from basic biology to signaling and disease, in FREE RADICAL BIOLOGY AND MEDICINE, 52(4), 725-734.
NOX5: from basic biology to signaling and disease.
Bedard Karen, Jaquet Vincent, Krause Karl-Heinz (2012), NOX5: from basic biology to signaling and disease., in Free radical biology & medicine, 52(4), 725-34.
NADPH oxidase (NOX) isoforms are inhibited by celastrol with a dual mode of action
Jaquet V, Marcoux J, Forest E, Leidal KG, McCormick S, Westermaier Y, Perozzo R, Plastre O, Fioraso-Cartier L, Diebold B, Scapozza L, Nauseef WM, Fieschi F, Krause KH, Bedard K (2011), NADPH oxidase (NOX) isoforms are inhibited by celastrol with a dual mode of action, in BRITISH JOURNAL OF PHARMACOLOGY, 164(2B), 507-520.
TNF-alpha blockade in chronic granulomatous disease-induced hyperinflammation: Patient analysis and murine model
Deffert C, Olleros ML, Yuan HP, Herrmann FR, Zekry D, Garcia I, Krause KH, Schappi MG (2011), TNF-alpha blockade in chronic granulomatous disease-induced hyperinflammation: Patient analysis and murine model, in JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 128(3), 675-677.
TNF-α blockade in chronic granulomatous disease-induced hyperinflammation: patient analysis and murine model.
Deffert Christine, Olleros Maria L, Huiping Yuan, Herrmann François R, Zekry Dina, Garcia Irene, Krause Karl-Heinz, Schäppi Michela G (2011), TNF-α blockade in chronic granulomatous disease-induced hyperinflammation: patient analysis and murine model., in The Journal of allergy and clinical immunology, 128(3), 675-7.
A Key Role for NOX4 in Epithelial Cell Death During Development of Lung Fibrosis
Carnesecchi S, Deffert C, Donati Y, Basset O, Hinz B, Preynat-Seauve O, Guichard C, Arbiser JL, Banfi B, Pache JC, Barazzone-Argiroffo C, Krause KH (2011), A Key Role for NOX4 in Epithelial Cell Death During Development of Lung Fibrosis, in ANTIOXIDANTS & REDOX SIGNALING, 15(3), 607-619.
NOX-4 is expressed in thickened pulmonary arteries in idiopathic pulmonary fibrosis
Pache JC, Carnesecchi S, Deffert C, Donati Y, Herrmann FR, Barazzone-Argiroffo C, Krause KH (2011), NOX-4 is expressed in thickened pulmonary arteries in idiopathic pulmonary fibrosis, in NATURE MEDICINE, 17(1), 31-32.
The NADPH Oxidase NOX2 Controls Glutamate Release: A Novel Mechanism Involved in Psychosis-Like Ketamine Responses
Sorce S, Schiavone S, Tucci P, Colaianna M, Jaquet V, Cuomo V, Dubois-Dauphin M, Trabace L, Krause KH (2010), The NADPH Oxidase NOX2 Controls Glutamate Release: A Novel Mechanism Involved in Psychosis-Like Ketamine Responses, in JOURNAL OF NEUROSCIENCE, 30(34), 11317-11325.
NADPH Oxidase 1 Modulates WNT and NOTCH1 Signaling To Control the Fate of Proliferative Progenitor Cells in the Colon
Coant N, Ben Mkaddem S, Pedruzzi E, Guichard C, Treton X, Ducroc R, Freund JN, Cazals-Hatem D, Bouhnik Y, Woerther PL, Skurnik D, Grodet A, Fay M, Biard D, Lesuffleur T, Deffert C, Moreau R, Groyer A, Krause KH, Daniel F, Ogier-Denis E (2010), NADPH Oxidase 1 Modulates WNT and NOTCH1 Signaling To Control the Fate of Proliferative Progenitor Cells in the Colon, in MOLECULAR AND CELLULAR BIOLOGY, 30(11), 2636-2650.
NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon.
Coant Nicolas, Ben Mkaddem Sanae, Pedruzzi Eric, Guichard Cécile, Tréton Xavier, Ducroc Robert, Freund Jean-Noel, Cazals-Hatem Dominique, Bouhnik Yoram, Woerther Paul-Louis, Skurnik David, Grodet Alain, Fay Michèle, Biard Denis, Lesuffleur Thécla, Deffert Christine, Moreau Richard, Groyer André, Krause Karl-Heinz, Daniel Fanny, Ogier-Denis Eric (2010), NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon., in Molecular and cellular biology, 30(11), 2636-50.
Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 5 (Nox5) Regulation by Angiotensin II and Endothelin-1 Is Mediated via Calcium/Calmodulin-Dependent, Rac-1-Independent Pathways in Human Endothelial Cells
Montezano AC, Burger D, Paravicini TM, Chignalia AZ, Yusuf H, Almasri M, He Y, Callera GE, He G, Krause KH, Lambeth D, Quinn MT, Touyz RM (2010), Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 5 (Nox5) Regulation by Angiotensin II and Endothelin-1 Is Mediated via Calcium/Calmodulin-Dependent, Rac-1-Independent Pathways in Human Endothelial Cells, in CIRCULATION RESEARCH, 106(8), 1363-1363.
Nicotinamide adenine dinucleotide phosphate reduced oxidase 5 (Nox5) regulation by angiotensin II and endothelin-1 is mediated via calcium/calmodulin-dependent, rac-1-independent pathways in human endothelial cells.
Montezano Augusto C, Burger Dylan, Paravicini Tamara M, Chignalia Andreia Z, Yusuf Hiba, Almasri Mahmoud, He Ying, Callera Glaucia E, He Gang, Krause Karl-Heinz, Lambeth David, Quinn Mark T, Touyz Rhian M (2010), Nicotinamide adenine dinucleotide phosphate reduced oxidase 5 (Nox5) regulation by angiotensin II and endothelin-1 is mediated via calcium/calmodulin-dependent, rac-1-independent pathways in human endothelial cells., in Circulation research, 106(8), 1363-73.
Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice
Weissmann N, Sydykov A, Kalwa H, Storch U, Fuchs B, Schnitzler MMY, Brandes RP, Grimminger F, Meissner M, Freichel M, Offermanns S, Veit F, Pak O, Krause KH, Schermuly RT, Brewer AC, Schmidt HHHW, Seeger W, Shah AM, Gudermann T, Ghofrani HA, Dietrich A, Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice, in NATURE COMMUNICATIONS, 3.
Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity.
Li Y, Mouche S, Sajic T, Veyrat-Durebex C, Supale R, Pierroz D, Ferrari S, Negro F, Hasler U, Feraille E, Moll S, Meda P, Deffert C, Montet X, Krause K-H, Szanto I, Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity., in International journal of obesity (2005).
Targeting Vascular NADPH Oxidase 1 Blocks Tumor Angiogenesis through a PPAR alpha Mediated Mechanism
Garrido-Urbani S, Jemelin S, Deffert C, Carnesecchi S, Basset O, Szyndralewiez C, Heitz F, Page P, Montet X, Michalik L, Arbiser J, Ruegg C, Krause KH, Imhof B, Targeting Vascular NADPH Oxidase 1 Blocks Tumor Angiogenesis through a PPAR alpha Mediated Mechanism, in PLOS ONE, 6(2).

Associated projects

Number Title Start Funding scheme
103725 ROS-Generating NADPH-Oxidases in colon and B-Lymphocytes 01.04.2004 Project funding
160220 NADPH oxidases as mediators in physiology and pathology: from hearing loss to neuroregeneration and immune modulation 01.04.2015 Project funding
141182 NOX enzymes: focus on the central nervous system 01.04.2012 Project funding
160220 NADPH oxidases as mediators in physiology and pathology: from hearing loss to neuroregeneration and immune modulation 01.04.2015 Project funding
139229 Platform for integrated mouse behavior (PIMB) 01.12.2011 R'EQUIP

Abstract

Background: In this grant application we propose to focus on the role of ROS-generating NOX enzymes in the central nervous system (CNS). It is now becoming clear that several members of the NOX family (in particular NOX1, NOX2, and NOX4) are expressed in the CNS, and hence contribute to CNS physiology and pathophysiology. The studies proposed in this grant application will be based on NOX-deficient rodents and on the use of human pluripotent stem cells.Working hypothesis: NOX-derived ROS are involved in developmental and/or signaling processes in the CNS. Under conditions such as psychosocial stress, drug toxicity (e.g. ketamine), or overshooting production of physiological mediators (e.g. angiotensin II), NOX enzymes of the central nervous system may lead to pathologies of the central nervous system and or participate in systemic disease.Specific Aims and Experimental Design: It is the allover aim of the project to understand the role of NOX enzymes as source of ROS generation in the CNS under physiological and pathophysiological conditions. Specifically, the project will focus on four questions. First, we will study the role of NOX enzymes on CNS development and function in vitro and in vivo. Both transgenic mice and induced pluripotent stem cells from NOX-deficient patients will be essential tools. Neuronal differentiation and NMDA receptor signaling will be central parameters to be analyzed. Second, we will study the relationship between NOX enzymes and angiotensin II receptor in the CNS and blood pressure regulation. Preliminary results suggest that in NOX1 deficient mice, there is a redistribution of the CNS AngII receptor. Essential tools for this study will be CNS application of AngII to NOX-deficient mice, and in vitro studies with primary culture of CNS cells (neurons, astrocytes). Read-outs will be ROS generation, AngII receptor localization, and blood pressure. Third, we will study the role of NOX enzymes in mediating the effect of psychosocial stress on ROS generation in the CNS and on the development of psychosis-like pathologies. Preliminary results suggest that social isolation in rats leads to a massive upregulation of NOX2 in several brain areas, but a loss of NOX1 in the prefrontal cortex. Mutant rat and mouse strains will be key tools. Animal behaviour, CNS gene expression and immunohistochemistry will be outcome parameters. Fourth, we will study the role of NOX enzymes in ketamine-induced psychosis. Preliminary results demonstrate that NOX2 deficiency protects mice from ketamine-induced behavioural deficits. Studies will be performed in transgenic mice, cultured rodent neurons, and engineered human neural tissues. Animal behaviour, ROS generation, and alteration in immunohistochemistry (loss of paravalbumin-positive neurons) will be the key read-outs. Expected Value of the Proposed Project: The studies proposed here should provide an increased understanding of redox biology of the central nervous system and the implication of NOX enzymes in development of pathologies including psychosis and hypertension.
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