Transcriptome and gene-network analyses to identify sex-specific differences in microglia inflammatory response during development

Type de poste
Dates
Durée du poste
Contrat renouvelable
Contrat non renouvelable
Date de prise de fonction
Date de fin de validité de l'annonce
Localisation
Adresse

Paris
France

Contacts
Andrée Delahaye-Duriez
Email du/des contacts
andree.delahaye@inserm.fr
Description

<p><strong>Summary : </strong></p><p>The project aims to identify sex-specific differences in microglial function that could explain, at least in part, differences observed in occurrences of neurological disorders in boys and girls (more particularly for neuropsychiatric conditions secondary to prematurity and neuroinflammation during brain development). We will adopt an integrated gene network approach using existing and newly generated omics data on a mouse model of perinatal neuroinflammation.</p><p><strong>Description :</strong></p><p>There are sex-specific differences in the incidence and outcome of many neurodevelopmental and neurodegenerative diseases. For most of these conditions, neuroinflammation is an important component of pathophysiology. Microglia, the CNS macrophage is one of the major players in neuroinflammatory processes. Sex-specific differences in microglial function could be crucial to the understanding of sex-specific differences in the emergence of neurological conditions as well as their treatment.</p><p>The project aims to identify sex-specific differences in microglial function that could explain, at least in part, differences observed in occurrences of neurological disorders in boys and girls. We will take advantage of the U1141 laboratory expertise in neuroinflammation during development [1]. Within the laboratory, a mouse model based on systemic injections of interleukin-1 beta (IL-1β) between P1 and P5 (Postnatal day 1 and 5) has been developed [2]. In this model, microglia were purified <em>ex vivo</em> to apply genome-wide transcriptomics analysis. Gene network analysis of the microglial transcriptomic response combined to protein-protein interactions and transcription factors analyses identified DLG4 as a hub protein in the microglial inflammatory response [3].</p><p>For the project, we will adopt an integrated gene network approach using existing and newly generated transcriptomics data on this same mouse model of perinatal neuroinflammation with 6 biological replicates for each condition (i.e n=24; IL-1β/PBS, male/female at P3). The identified gene networks and molecular pathways will be compared and crossed-checked with other published genome-wide expression data of microglia in male and female mice (n=60, RNAseq GSE99622) and during development (n=91, RNAseq GSE79812). Understanding the sex-specific molecular mechanisms regulating the activation of immature microglia in the developing brain could help to develop effective therapies aimed at preventing the onset of brain damage and neurodevelopmental disorders.</p><p>The selected candidate will be embedded in the group &ldquo;<a href="http://neurodiderot.org/index.php/en/delahaye-en/">Integrative genomics in Neurodevelopment</a>&rdquo;<br />that gathers researchers working on neurodevelopmental disorders using gene-network based approaches [4], [5], [6]. He/she will have the opportunity to gain a high level of competence in the highly demanded area of transcriptome analysis.</p><p><strong>Expected skills :&nbsp;</strong></p><p>The ideal candidate would combine</p><p>- Proficiency with at least one programming language (R and/or Python) and with bash/shell scripting.</p><p>- Computational background to easily adapt to a UNIX environment in a high-computing cluster</p><p>- Interest/skills in bioinformatics data analysis</p><p>- Abilities to work independently and collaboratively</p><p><strong>How to apply?</strong></p><p>Interested candidates should submit an application either in English or French to&nbsp;<a href="mailto:andree.delahaye%40inserm.fr">andree.delahaye@inserm.fr</a>&nbsp;… a detailed CV and a motivation letter.<br />The desired starting date is anytime between January and May 2019.</p><p><strong>Références :</strong></p><p>[1]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; H. Hagberg et al. &ldquo;The role of inflammation in perinatal brain injury,&rdquo; <em>Nat. Rev. Neurol.</em>, 2015.</p><p>[2]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; G. Favrais et al. &ldquo;Systemic inflammation disrupts the developmental program of white matter,&rdquo; <em>Ann. Neurol</em>., 2011.</p><p>[3]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; M. L. Krishnan et al. &ldquo;Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants,&rdquo; <em>Nat. Commun.,</em> 2017.</p><p>[4]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; A. Delahaye-Duriez et al. &ldquo;Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery,&rdquo; <em>Genome Biol</em>., 2016.</p><p>[5]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; M. R. Johnson et al. &ldquo;Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.,&rdquo; <em>Nat. Neurosci.</em>, 2015.</p><p>[6]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; P. K. Srivastava et al. &ldquo;A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target,&rdquo; <em>Nat. Commun.</em>, 2018.</p><p>&nbsp;</p><p>&nbsp;</p><br/>
Lieu: <p>INSERM Neurodiderot UMR1141/PROTECT<br />Hôpital Robert Debré<br />Bâtiment Bingen, 3<sup>ème</sup>&nbsp;étage<br />48 Boulevard Sérurier<br />75019 Paris<br /><a href="https://www.neurodiderot.com/">https://www.neurodiderot.com/</a></p><p>…;
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Laboratoire: INSERM U1141