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NADPH oxidases as mediators in physiology and pathology

English title NADPH oxidases as mediators in physiology and pathology
Applicant Krause Karl-Heinz
Number 179478
Funding scheme Project funding (Div. I-III)
Research institution Département de Pathologie Clinique Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Physiology : other topics
Start/End 01.04.2018 - 31.03.2023
Approved amount 1'008'000.00
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All Disciplines (2)

Discipline
Physiology : other topics
Pathophysiology

Keywords (6)

Induced pluripotent stem cells; Inner ear; Infection; Inflammation; Oxidative stress; Brain

Lay Summary (German)

Lead
Sauerstoffradikale können zu Gewebsschäden und verschiedenen Krankheiten führen, sowie zum Alterungsprozess beitragen. Mein Forschungslabor war an der Entdeckung von körpereigene Enzymen welche Sauerstoffradikale produzieren massgeblich beteiligt und arbeitet seit vielen Jahren an diesem Thema. Es gibt sieben solcher Enzyme, und man bezeichnet sie als NOX NADPH oxidasen. Der jetzige Forschungsantrag addressiert die Rolle von NOX NADPH oxidases in: i) Staphyolokokkeninfektionen, ii) in Nervenstammzellen, und iii) in Innerohrschwerhörigkeit.
Lay summary
NADPH oxidasen sind Enzyme des menschlichen Körpers welche Sauerstoffradikale produzieren. Sauerstoffradikale können für unseren Körper schädlich sein. Man denkt dass sie zur Entstehung von gewissen Krankheiten beitragen und auch dass sie eine Rolle im Alterungsprozess spielen. Aber Sauerstoffradikale spielen auch eine wichtige Rolle für die normale Funktion unseres Körper. Wir wissen heute, dass sie wichtig sind für die Immunantwort gegen Bakterien und Pilze, für die Biosynthese von gewissen Substanzen unseres Körpers (z.B. Schilddrüsenhormone), sowie für die Feinregulierung der Funktion von menschlichen Zellen. Mein Forschungsantrag fokusiert auf 3 Themen im Bereich der Produktion von Sauerstoffradikalen durch NADPH oxidasen:
i) Warum haben Patienten mit einem genetischen Defekt in der NADPH oxidase NOX2 ein stark erhöhtes Risiko durch das Bakterium Staphyloccus aureus infiziert zu werden. Wir denken dass die von NOX2 produzierten Sauerstoffradikale die Genexpression in den Bakterien so verändern, dass die Infektion durch unseren Körper kontrolliert werden kann.
ii) Die NADPH oxidase NOX2 ist zwei Regionen des Gehirns stark exprimiert. Es handelt sich um Hirnregionen welche reich in Stammzellen sind, und welche zur Neuroregeneration beitragen. Wir werden untersuchen durch welche Mechanismen NOX2 zur Regeneration des Gehirns beiträgt und hoffen dass diese Untersuchengen zu neuen Konzepten in der Hirnregeneration führen werden.
iii) Die NADPH oxidase NOX3 ist hauptsächlich im Innenohr zu finden. Es gibt erste Hinweise dafür dass Überaktivität von NOX3 im Innerohr zu Schwerhörigkeit führen kann. Wir werden die Rolle von NOX3 in verschiedenen Situation welche Schwerhörigkeit auslösen (Medikamente, Lärm, Alter) untersuchen, und molekularbiologische Methoden für innovative Therapien entwickeln.
Direct link to Lay Summary Last update: 11.04.2018

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Number Title Start Funding scheme
160220 NADPH oxidases as mediators in physiology and pathology: from hearing loss to neuroregeneration and immune modulation 01.04.2015 Project funding (Div. I-III)

Abstract

NOX NADPH oxidases are a family of enzymes whose main biochemical function is the production of reactive oxygen species (ROS). In mammals, the family consists of seven isoforms (NOX1-5, DUOX1,2) with a broad range of biological functions: from host defense, to cellular signaling and biosynthesis. Over-activation of NOX enzymes can lead to oxidative stress-driven disease (e.g. fibrosis, cardiovascular disease, neurodegeneration). In this grant application, we will focus on three topics within the NOX field, building on previous work from our group. NOX2 and host defense against S. aureus: Patients with NOX2 deficiency (chronic granulomatosis diseases, CGD) typically suffer from chronic and recurrent S. aureus infections. This is astonishing as S. aureus has a strongly developed antioxidant defense and is particularly resistant against killing by ROS. So why is the ROS-generating phagocyte NADPH oxidase NOX2 particularly relevant for the defense against this bacterium? Our working hypothesis is that ROS at sub-lethal concentrations lead to dysregulation of bacterial gene expression and thereby to a decreased bacterial fitness. To test this, we propose to investigate ROS-regulated genes in S. aureus and their role in bacterial fitness. We also propose to screen a library of 1,900 isogenic S. aureus transposon mutants for their sensitivity to ROS. Mutants of “ROS-relevant” genes will be tested for their pathogenicity in a skin infection model using wild-type and NOX2-deficient mice. Our study is designed to better understand - and ultimately to better treat - S. aureus pathology in CGD patients. Notably, this approach will also allow a better understanding of redox-sensitive host-pathogen interaction in S. aureus infection.NOX2 in neural stem/precursor cells (NSPCs): Unexpectedly, the phagocyte NADPH oxidase NOX2 is highly expressed in neurogenic brain regions. This is not due to the presence of phagocytes, but rather due to NOX2 expression in NSPCs. In mouse brain neurogenic regions, as well as during neural differentiation of human induced pluripotent stem cells, NOX2 deficiency leads to a decrease in the pool of proliferating NSPCs. Here we propose to study the underlying mechanisms leading to this phenotype. We will investigate three possible (not mutually exclusive) mechanisms: i) NOX2 acts through redox-sensitive gene expression; ii) NOX2 acts through alterations of the redox-sensitive kinase/phosphatase equilibrium, and iii) NOX2 has redox-independent effects through its impact on intracellular pH and cellular membrane potential. Our findings should allow a better understanding of how NOX2 plays a role in stem cell biology. They also are likely to provide novel insights into the regulation of the size of the NSPC pool and provide novel strategies for stem cell-targeting therapies in the central nervous system. Development of NOX-targeted molecular therapies for hearing loss: NOX3 is highly expressed in the inner ear. While the reason for its expression in the cochlea remains enigmatic, there is increasing evidence that over-activation of NOX3 is involved in hearing loss, in particular in the context of chemotherapy with cisplatin. During the previous grant period, our team produced results showing that NOX3 also plays an important role in noise-induced and age-associated hearing loss. For the next grant period, we propose to follow up on this research and address two relevant points. First, we will investigate the relative role of NOX3 as compared to other NOX isoforms in noise-induced hearing loss. Second, we will use a model of age-associated hearing loss in A/J mice to develop a molecular therapy of hearing loss based on vector-delivery of therapeutic minigenes carrying anti-NOX miRNA. The studies proposed here should allow to define the optimal profile for a NOX-targeted inner ear therapy (narrow NOX3 targeting vs. broad NOX targeting). It will also lay the basis for a vector-mediated delivery of miRNA for the knock-down of genes with a pathogenic role in inner ear diseases.
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