Autophagy-inflammasome interplay in Wiskott-Aldrich syndrome (360G-Wellcome-201250_Z_16_Z)

£237,672

Background: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder associated with haemorrhage and malignant potential. 70-80% also suffer severe inflammatory complications. Despite excellent survival post stem cell transplant, 30% of children have ongoing autoinflammation. Emerging evidence indicates that the actin cytoskeleton has an important role in autophagy, and inflammasome activity is intricately linked. Aims: Define the molecular role of Wiskott-Aldrich syndrome protein (WASp) in autophagy and inflammasome activation and investigate the impact of potential therapies. Methods: WASp knockout macrophage cell lines will be generated using CRISPR technology and GFP-tagged WASp introduced using lentiviral transduction. ATP, starvation and infection will be used to stimulate autophagy/ inflammasome activation. Cellular events will be followed by qPCR, western blotting and flow cytometry. Cellular localisation will be investigated by high resolution microscopy (epifluorescent, confocal, super resolution). Transcriptomics will be used to identify the impact of WASp deficiency on cellular gene expression. Implications: Inflammasome dysregulation has been implicated in a wide range of disease processes. Investigation of inflammasome dysfunction mechanisms in WAS will facilitate better understanding of the actin cytoskeleton role in the autophagy-inflammasome axis, providing therapeutic implications far beyond WAS.

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Grant Details

Amount Awarded 237672
Applicant Surname Rivers
Approval Committee Clinical Interview Committee
Award Date 2016-03-02T00:00:00+00:00
Financial Year 2015/16
Grant Programme: Title Research Training Fellowship
Internal ID 201250/Z/16/Z
Lead Applicant Dr Elizabeth Rivers
Partnership Value 237672
Planned Dates: End Date 2019-12-31T00:00:00+00:00
Planned Dates: Start Date 2016-09-05T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London
Sponsor(s) Prof Adrian Thrasher