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Appel à candidatureContrat doctoral 2019UNIVERSITE CONFEDIE_ALIE

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Document à remettre (mail accepté) à l'école doctorale avant le 15 février 2019

Intitulé du sujet:

Impact of Sonic Hedgehog pathway upon astrocyte and pericyte crosstalk in Alzheimer' s disease

Laboratoire d'accueil :

Nom:

Art. 16 - Arrêté du 25 mai 2016 Co-encadrant de thèse:Directeur de thèse (HDR): Co-directeur de thèse:Nom: Guylène PAGE Nom: Vincent THOREAUguylene.page@univ-poitiers.fr vincent.thoreau@univ-poitiers.frTel: OS 49 36 62 60 Tel: OS 49 45 49 78Taux d'encadrement prévu: 50% Taux d'encadrement prévu: 50%Taux d'encadrement de thèses en Taux d'encadrement de thèses encours au 1er février 2019 cours au 1er février 2019Nom du doctorant: AUCUN Nom du doctorant: Gara BRAJADENTAà ...% à 50 % soutenance en mai 2019

-------@Tel:Taux de contribution prévu: _ %Taux d'encadrement de thèses encours au 1er février 2019Nom du doctorant:à ...%

Description du sujet de thèse: (Maximum recto)

Alzheimer's disease (AD) patients suffer from dysfunctions of the blood-brain barrier'(BBB): notably, increased permeability

of endothelial cells contributes to blood vessel fragility, inflammation and eventually neurodegeneration. Arnong the BBB

cells, astrocytes and pericytes promote the barrier integrity and functionality. ln AD, both cells attend amyloid peptide

clearance from the brain, but are also involved in neuroinflammation. Moreover, pericyte loss then results in BBB breakdown.

Mutual regulation pathways between either astrocytes or pericytes, and endothelial cells have been extensively studied. ln

particular, astrocytes release Sonic Hedgehog (Shh) protein, promoting BBB formation and integrity. This control is disrupted

in inflammatory conditions. Shh is also an endogenous neuroprotective signal. However, the crosstalk between astrocytes

and pericytes remains poorly characterized.

ln this project, we plan to investigate the involvement ofShh signaling pathway in astrocyte and pericyte crosstalk. The focus

will be held on the control of BBB functionality in AD. We will use two ex-vivo mou se BBB models developed in the

laboratory: firstly, celllines (endothelial cells, pericytes) were generated and characterized from an AD (APPsweIPSldE9)

transgenic mouse model and its WT counterpart. Astrocytes were extracted from brain mice. Secondly, we will validate major

results in primary culture combinations of cells extracted from the brain ofWT versus AD mice aged from 3 to 12 months.To

discriminate the involvement of the different cells, we can establish the model without pericyte or astrocyte in inflammatory

environment or not. The impact ofShh pathway will be studied using chemical inhibitors or by downregulating the expression

of actors of the pathway. We will evaluate the microenvironment composition (Shh, growth factors, ApoE,

metalloproteinases ... ) and the expression of tight junction proteins, transporters and Shh pathway actors, by qRT-PCR,

western, ELISA and immunofluorescence. We will also study the functionality of the BBB by Dextran-FITC permeability,

Rhodamine efflux and glucose uptake assays. This project will contribute to find elues originating from astrocytes and/or

pericytes, in order to improve the impairrnents found in AD, regarding BBB tightness and functions.

Ecole Doctorale SBS4rue Michel Brunet - Bât B27 - Chimie

hltp:! /www.u-Idevinci.fr/sbs/Tel:05 49 45 35 88

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Appel à candidatureContrat doctoral 2019UNIVERSITE CONFIOt:ttAlE

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Co-directeur de thèse:Si natures:

Directeur de thèse:

Pr Guylène PAGE

Directeur de laboratoire:

Pr Guylène PAGE Laboratoire EA3808 . NEUVACODPôle Biologie Santé

1 rue Georges Bonnet TSA 5110686073 POITIERS Cedex 9

Ecole Doctorale SBS4rue Michel Brunet - Bât B27 - Chimie

http://www.u-Idevinci.fr/sbs/TeI:05 49 45 35 88