DS0401 - Une nouvelle représentation du vivant

Macrophage ontogeny and homeostasis in obesity and diabetes – FATMAC

FATMAC

Macrophage ontogeny and homeostasis in obesity and diabetes

objectives

1. Map the ontogeny and homeostasis of MF during metabolic stress. <br />2. Determine the specific role of proliferative MF in metabolic stress and T2D. <br />3. Assess the role of c-Jun in MF homeostasis during metabolic stress and T2D.

1. Map the ontogeny and homeostasis of MF during metabolic stress.
We proposed to use a unique genetic fate-mapping tool, the Ubow mouse (Ghigo et al., 2013), to investigate the ontogeny and homeostasis of MF in metabolic tissues in situ under conditions of metabolic stress. This mouse allows the simultaneous mapping of MF ontogeny, proliferation and anatomical localization.
2. Determine the specific role of proliferative MF in metabolic stress and T2D.
We have generated a genetic tool to allow the specific isolation of actively proliferating cells in tissues based on the recently developed CycB1-GFP fusion reporter (Klochendler et al., 2012). We intended to use this mouse to isolate and define the transcriptional signature of proliferating MF compared with their quiescent counterparts in different tissues under metabolic stress. We will also modify this strategy to develop a genetic tool allowing the specific and inducible ablation of proliferating MF in vivo, based on macrophage-restricted expression of CycB1-DTA (diphtheria toxin A) fusion. We will use this strategy to ablate proliferative MF and assess their contribution to parameters of metabolic stress and the development of T2D.
3. Assess the role of c-Jun in MF homeostasis during metabolic stress and T2D.
Based on our preliminary data we will test the hypothesis that the AP-1 factor c-Jun regulates MF proliferation during metabolic stress. Inactivation of this transcription factor and the subsequent effects on MF accumulation and activation during metabolic stress will give us important insights into the molecular mechanisms that regulate MF function in the development of T2D.

1. Map the ontogeny and homeostasis of MF during metabolic stress.
Progress ; Our previous studies have shown that the Ubow transgene is not efficiently activated in all tissue macrophages with the macrophage-specific cre transgenic mice that we have used. We are currently developing new cre mice to repeat these experiments which should be available in by the end of this year.
2. Determine the specific role of proliferative MF in metabolic stress and T2D.
Progress ; Our previous studies have shown that the CycB1-reporter mouse is not effective to measure macrophage proliferation, due to low levels of expression of the fluorescent reporter protein. We are now trying to establish metabolic labeling protocols to track macrophage proliferation in tissues.
3. Assess the role of c-Jun in MF homeostasis during metabolic stress and T2D.
Progress ; Our previously reported data showed a siginificant role for Jun in accumulation of mature tissue resident macrophages in adult healthy mice. Interestingly, Jun does not affect the accumulation of monocytes or monocyte-derived macrophages, suggesting Jun may specifically affect the seeding of tissue macrophages of embryonic origin or the persistence of mature terminally differentiated macrophages. We are now extending this analysis to metabolic tissues during stress.

We hope these studies will further our understanding of macrophage biology under conditions of metabolic stress and identify new molecular targets with potential for therapeutic intervention in metabolic diseases such as T2D.

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Metabolic diseases, such as type 2 diabetes (T2D) and atherosclerosis, represent the major healthcare issue of the 21st century in western society. One of the important underlying factors in the development of these diseases is metabolic stress caused by high fat diet. Macrophages are strongly linked with the pathogenesis of metabolic diseases, however the ontogeny and homeostasis of macrophages in the context of metabolic stress has not been studied. In this project we will examine the fundamental basis for macrophage homeostasis in both diet-induced and genetic models of metabolic disease and T2D, using state-of-the-art imaging and molecular techniques in vivo to track macrophage ontogeny. We will investigate the molecular mechanisms that regulate macrophage homeostasis in these conditions, and specifically explore the role of the transcription factor c-Jun in macrophage homeostasis and function during metabolic stress and development of T2D. We hope these studies will further our understanding of macrophage biology under conditions of metabolic stress and identify new molecular targets with potential for therapeutic intervention in metabolic diseases such as T2D.

Project coordinator

Monsieur Toby LAWRENCE (Centre National de la Recherche Scientifique délégation Provence et Corse_Centre d'Immunologie de Marseille Luminy)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM DR PACA et CORSE_C3M Institut National de la Santé et de la Recherche Médicale_Institut Mediterranéen de la Médecine Moléculaire
CNRS DR12_CIML Centre National de la Recherche Scientifique délégation Provence et Corse_Centre d'Immunologie de Marseille Luminy

Help of the ANR 450,000 euros
Beginning and duration of the scientific project: September 2014 - 48 Months

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