Gasdermin D is a novel effector in the extrinsic apoptosis pathway

Projektinformationen

Inflapoptosis

ID Finanzhilfevereinbarung: 838252

DOI

10.3030/838252

Das Projekt endete am 30 September 2020

EK-Unterschriftsdatum 10 April 2019

Startdatum 1 September 2019

Enddatum 31 August 2021

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 191 149,44

EU-Beitrag

€ 191 149,44

Koordiniert durch

UNIVERSITE DE LAUSANNE
Switzerland

Periodic Reporting for period 1 - Inflapoptosis (Gasdermin D is a novel effector in the extrinsic apoptosis pathway)

Berichtszeitraum: 2019-09-01 bis 2021-08-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Gasdermin D (GSDMD) is a recently described pore-forming protein that is important for host defence against infection. However, emerging studies also implicate GSDMD in a variety of inflammatory diseases through poorly characterised mechanisms.
The aim of this study is to investigate the molecular and cellular mechanisms by which GSDMD promote inflammatory disease, so that better drug candidates can be identified in future. Here, we characterised the molecular mechanisms by which GSDMD promotes
tumour necrosis factor(TNF)-driven diseases. We show that caspase-8-dependent GSDMD activation promotes TNF-driven disease in mice. Our study thus uncovers novel drug targets for TNF-driven diseases.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

-Generation of caspase-3-uncleavable GSDMD mouse model
-Demonstration that caspase-3-uncleavable GSDMD mouse do not suffer from auto-inflammatory disease
-Validated that GSDMD activation promotes anti-microbial defence
-Validated that GSDMD activation promotes TNF-driven lethality

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

TNF-mediated diseases were traditionally believed to be solely driven by necroptosis, a form of necrotic death. Multi labs and biotech companies are developing such inhibitors to block these pathways, however, there are limited success.
Our work has now uncovered GSDMD, as a novel player in TNF-driven disease, therefore providing a new drug target.

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