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Inflammatory signals of cell death

Project description

Investigation of the fundamental principles of sterile inflammation

Inflammation represents a natural mechanism to restore tissue homeostasis, while its deregulation causes disease. The ERC-funded FIREALARM project will focus on the fundamental mechanisms of the physiological origin of inflammation using organismal-, cellular- and molecular-level approaches. The project will examine the central hypothesis that endogenous intercellular signalling proteins drive sterile inflammation and shift homeostatic stable to non-resolving chronic states. Newly developed secretomics, including cell type specific mass spectrometry, will identify inflammatory signals in vitro and in vivo. The goal is to achieve a better understanding of the molecular and organismal signalling circuits governing homeostasis and develop strategies to treat chronic conditions.

Objective

Inflammation is a natural mechanism to restore tissue homeostasis, and its deregulation causes human disease. The programmed cell death form pyroptosis elicits inflammation in a cell-autonomous and non-autonomous fashion by releasing cytokines and ‘danger’ signals. Intriguingly, immune pathology independent of cytokines has alluded to unexplored signaling circuits between cells regulating pyroptotic inflammatory reactions.
FIREALARM addresses the fundamental question of the physiological origin of inflammation using convergent system-wide, organismal, cell biological, and molecular approaches. We will test the central hypothesis that endogenous intercellular signaling proteins drive sterile inflammation and shift homeostatic stable to non-resolving chronic states. We will determine paracrine activities of pyroptosis by systematic, iterative ablation of molecule release from dying and perception pathways of sentinel cells. In a complementary approach, we will identify inflammatory signals in vitro and in vivo by newly developed cell type-specific mass spectrometry-based secretomics technologies. Holistic views of intercellular signaling proteins, their exposure, and modification will determine the molecular language orchestrating communication networks between cells and enable the recognition of signals initiating, amplifying, and resolving inflammation. We will achieve a new level of molecular and organismal understanding of intercellular circuits governing homeostasis and conceive strategies to revert chronic conditions. Emerging inflammatory cell death markers will stratify molecular etiology and outcome of patients with sterile inflammatory diseases.
Together, FIREALARM tackles the fundamental principles of sterile inflammation relevant for understanding the pathogenesis of chronic metabolic and age-related disorders.

Host institution

UNIVERSITATSKLINIKUM BONN
Net EU contribution
€ 1 991 250,00
Address
VENUSBERG-CAMPUS 1
53127 Bonn
Germany

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Region
Nordrhein-Westfalen Köln Bonn, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 1 991 250,00

Beneficiaries (1)