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Mechanistic Studies on Carbon Monoxide (CO)-Induced Modulation of Mitochondrial Function in Neuroinflammation

Objective

Neuroinflammation plays a crucial role in the development and progression of neurodegenerative diseases such as Alzheimer’s or ischemic stroke. The inflammatory response is coordinated by resident cells (microglia) that upon activation produce pro-inflammatory mediators including cytokines, chemokines and reactive oxygen species. Identification of small molecules that alleviate microglia inflammation is therefore pivotal in uncovering feasible therapeutic approaches to treat brain disorders. Emerging evidence indicates that carbon monoxide (CO), which is endogenously produced in cells by the enzyme heme oxygenase-1 (HO-1), functions as an important signaling mediator endowed with strong anti-inflammatory activities. However, the mode(s) by which CO elicits these effects remains to be elucidated. Although CO is a renowned inhibitor of mitochondrial respiration at high concentrations, recent results reveal that low doses of CO positively modulate mitochondrial function. The current proposal aims to investigate how the interaction of CO with mitochondria affects its anti-inflammatory activity in microglia. Innovative chemical entities and methodological approaches will be employed to dissect the different functions of CO in this context, including: 1) CO-releasing molecules, which deliver precise amounts of CO to biological systems; 2) a new class of hybrid molecules composed of a CO-releasing moiety coordinated to an electrophilic structure known to induce HO-1 expression; 3) a Seahorse Analyser to perform an in-depth biochemical analysis of the effect(s) of CO on mitochondrial bioenergetics and how this may lead to a reduced inflammatory response, and; 4) whole-genome transcriptome profiling of primary microglia cells focusing on the effects of CO on genes involved in cell metabolism and inflammation. This project will provide the first comprehensive investigation into the networks that are involved in the anti-inflammatory activity of this ephemeral signaling gas.

Field of science

  • /medical and health sciences/basic medicine/neurology/stroke
  • /engineering and technology/environmental engineering/energy and fuels/fossil energy/gas
  • /natural sciences/chemical sciences/inorganic chemistry/inorganic compounds
  • /natural sciences/biological sciences/cell biology/cell metabolism
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes
  • /medical and health sciences/basic medicine/neurology/alzheimer

Call for proposal

FP7-PEOPLE-2013-IEF
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Address
Rue De Tolbiac 101
75654 Paris
France
Activity type
Research Organisations
EU contribution
€ 194 046,60
Administrative Contact
Laurie Louis-Joseph (Ms.)