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Involvement of the endoplasmic reticulum stress response in lung dendritic cell function and inflammatory lung diseases

Objective

Dendritic cells (DCs) are essential for the instruction of adaptive immunity and for the pathogenesis of many inflammatory lung diseases. These cells sense the presence of exogenous and endogenous signals and initiate an immune response that is matched to the nature of the offending insult. Many environmental triggers of inflammatory lung diseases including allergens, cigarette smoke, fine dust particles or microbes induce signs of endoplasmic reticulum (ER) stress in lung cells. ER stress is characterized by an accumulation of unfolded proteins in the ER, which leads to an intracellular signalling cascade named unfolded protein response (UPR). Although it has been recently shown that the UPR is a constitutively active signalling pathway in DCs, it is unknown whether activation of the ER stress pathways in DCs contributes to the regulation of immune responses at mucosal sites.
The foundations of this project lie in three crucial aspects of DCs: 1) DCs are important sensors of exogenous and endogenous danger signals in the lung, 2) DCs are active targets of the ER stress response, and 3) DCs are central coordinators of the immune response that leads to asthma. Based on these three aspects, we hypothesize that the presence of unfolded proteins in the ER acts as an endogenous danger signal that plays a fundamental role in the function of lung DCs and their involvement in inflammatory lung diseases.
With this project, we will gain firm knowledge about the cellular events that coordinate the ER stress response to environmental triggers in DCs. By using innovative approaches, we will analyze the relevance of the UPR signalling in lung DC subsets in vivo. In addition, in light of previous findings reporting the genetic association between polymorphisms in the ER stress regulator ORMDL3 and asthma, we will formally evaluate the role of ORMDL3 in the development of lung inflammation.

Call for proposal

FP7-PEOPLE-2010-IEF
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Coordinator

UNIVERSITEIT GENT
Address
Sint Pietersnieuwstraat 25
9000 Gent
Belgium

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Activity type
Higher or Secondary Education Establishments
Administrative Contact
Saskia Vanden Broeck (Ms.)
EU contribution
€ 163 300