Periodic Reporting for period 1 - Inflapoptosis (Gasdermin D is a novel effector in the extrinsic apoptosis pathway) Reporting period: 2019-09-01 to 2021-08-31 Summary of the context and overall objectives of the project 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. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far -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 Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) 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. screenshot-2020-12-07-at-5-13-16-pm.png
