Macrophages cérébraux, lipides et inflammation

Offre de thèse

Date limite de candidature

31-05-2025

Date de début de contrat

01-10-2025

Directeur de thèse

MALKINSON Guy

Encadrement

The PhD student will be in charge of carrying out the overall project, receiving continuous scientific advice and guidance from the supervisors and benefiting from the team's scientific and technical expertise. The student is expected to acquire a DU in animal experimentation to be able to work with laboratory animals. The PhD student will be supported throughout his/her PhD: Weekly meetings with the advisors will be held to discuss scientific, technical and organizational aspects. The PhD student will compile his weekly results, and plan with the advisor the experiments to follow. The doctoral student will receive appropriate training to ensure the smooth running of their doctoral project (microscopy, flow cytometry, etc.). Personnel within the unit are specialist in flow cytometry and can provide assistance and guidance when required. The doctoral student will actively participate in Doctoral School days, and will have the opportunity to submit and present his/her work at national and international conferences. The PhD student will play an active role in writing the publications resulting from his/her work. The doctoral student will have the opportunity to follow training courses in line with his/her post-doctoral career plans.

Type de contrat

Concours pour un contrat doctoral

Candidater à cette offre

école doctorale

BioSE - Biologie Santé Environnement

équipe

contexte

The cerebrovascular network provides essential energy to billions of brain cells, and their activity generates large amounts of by-products that must be removed in order to maintain a homeostatic environment. In the brain, passage of molecules across the endothelium is tightly regulated by the blood-brain-barrier (BBB). Removal of by-products from brain tissue is achieved by the glymphatic system, involving flow of cerebrospinal fluid (CSF) in perivascular spaces (PVS) around blood vessels. Vascular macrophages (VAM) are found in the PVS, around cerebral blood vessels, on the abluminal side of the endothelium, and they express several hallmark specific receptors. At the anatomical level, brain-region specific vascular macrophages are found in the postnatal mouse brain, and sub-populations of these macrophages appear in an Alzheimer's disease (AD) mouse model, raising the possibility that these receptors are differentially modulated in AD and may mediate different macrophage activities. Vascular macrophages regulate various aspects of brain physiology, as they phagocytose large molecules and lipids, and mediate CSF dynamics, BBB properties and recovery from stroke. In response to lipid-enriched diets, they become swollen and rich in dark inclusions of various sizes, and contain large intracellular inclusions as the result of substantial lipid uptake. In the hypothalamus, a key brain region controlling metabolism and energy homeostasis, this macrophage phenotype was suggested to prevent excessive lipid/free fatty acid accumulation in the extracellular space, which can be detrimental to neurons and other cells. A less-explored aspect of vascular macrophages is their role in diet-induced metabolic diseases linked to high levels of dietary fats and exhibiting obesity and inflammation. Diet-induced obesity (DIO) induces BBB dysfunction and lipid perturbations across several brain regions, and is furthermore associated with low-grade chronic inflammation reflecting a failure in resolution of inflammation. DIO leads to pronounced inflammation, and cerebral macrophages mediate obesity-associated neuro-inflammation. Specialized pro-resolving mediators (SPM) and their receptors are known to play a central role in resolution of inflammation, to reduce neuro-inflammation and metabolic and inflammatory DIO-effects, and to enhance phagocytic activity in vascular-associated aortic macrophages. Thus, evidence from different studies links macrophage activity with lipid levels, inflammation and SPM-mediated resolution of inflammation.

spécialité

Sciences de la Vie et de la Santé - BioSE

laboratoire

DCAC - Défaillance cardiovasculaire aigue et chronique

Mots clés

Cerveau, Macrophages, Lipides, Inflammation, Vasculaire

Détail de l'offre

Le réseau vasculaire cérébral est essentiel à la préservation des fonctions cérébrales. Des macrophages vasculaires spécialisés répondent aux aspects fondamentaux de la physiologie cérébrale tels que le flux du liquide céphalo-rachidien, les propriétés de la barrière hémato-encéphalique, le rétablissement après des conditions pathologiques et l'inflammation, et jouent un rôle de médiateur dans ces aspects. L'alimentation riche en graisses (HFD) entraîne une prise de poids importante et une inflammation chronique de bas grade, et chez les souris, elle est associée à une modification des profils lipidiques dans le cerveau. Chez les souris nourries à l'HFD, des signes inflammatoires se développent dans le cerveau, mais le rôle des macrophages vasculaires dans le processus inflammatoire et sa résolution est très peu décrit. Des médiateurs pro-résolution spécialisés et leurs récepteurs jouent un rôle central dans la résolution de l'inflammation, et ce projet examinera comment ces médiateurs et leurs récepteurs agissent sur les macrophages vasculaires dans les conditions physiologiques qui se développent en cas de modification des niveaux de lipides alimentaires. Ce projet utilisera des études histologiques, moléculaires et fonctionnelles pour établir cette réponse physiologique dans le cerveau, dans le but d'identifier de nouveaux éléments qui interviennent dans ce processus.

Keywords

Brain, Macrophages, Lipids, Inflammation, Vascular

Subject details

The cerebrovascular network is crucial for preserving proper brain functions. Specialized brain vascular macrophages respond to and mediate fundamental aspects of brain physiology such as flow of cerebrospinal fluid, blood-brain-barrier properties, recovery from pathological conditions and inflammation. High-fat diet (HFD) leads to significant weight gain and to low grade chronic inflammation, and in mice is associated with altered lipid profiles in the brain. In HFD-fed mice, inflammatory signs develop in the brain, but little is known on the role of vascular macrophages in the inflammatory process and its resolution. Specialized pro-resolving mediators and their receptors play a central role in resolution of inflammation, and this project will examine how these mediators and their receptors act on vascular macrophages during the physiological conditions that develop in altered dietary lipid levels. This project will use histological, molecular and functional studies to establish this physiological response in the brain, with the aim of identifying novel elements that mediate this process.

Profil du candidat

M2 en sciences de la vie (biochimie, neurosciences, biologie cellulaire, physiologie, immunologie) ; une expérience en expérimentation animale (souris). Compétences en histologie, biochimie (ELISA, analyses lipidiques), biologie cellulaire et moléculaire, microscopie. Veuillez indiquer si vous avez obtenu une certification pour l'expérimentation animale ou l'équivalent. Inclure une liste de références.

Candidate profile

Master's degree in life sciences (biochemistry, neuroscience, cell biology, physiology, immunology); experience with mouse models is a plus. Skills in histology, biochemistry (ELISA, lipid analyses), cell and molecular biology, microscopy. Please indicate if certification for animal experimentation or equivalent has been acquired. Include list of references.

Référence biblio

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