Periodic Reporting for period 1 - E-T1IFNs (Elaboration of the type I interferonopathies)
Reporting period: 2018-11-01 to 2020-04-30
Set against the absence of a routine assay in clinical medicine for the detection of upregulated type I interferon, the current application addresses major questions in the developing T1IFN field. Analogous to other screening strategies (e.g. using mouse ENU mutagenesis or yeast gene deletion series), we have established a pipeline for the systematic identification of human mutant states predisposing to upregulated type I interferon signalling. Such an approach will allow for the comprehensive definition of important themes in interferon biology, informing our understanding of anti-viral signalling and self-non-self discrimination. Furthermore, these studies will have direct translational benefit - since the identification of a phenotype as a T1IFN implies the possibility of therapy to reduce type I interferon levels and / or block interferon signalling.
1. The definition of three genotypes predisposing to type I interferon dysregulation due to a disturbance of chromatin biology.
2. Interrogation of the role of the ER-Golgi axis in the regulation of type I interferon signalling.
3. Definition of the molecular and phenotypic landscape related to mutations in IFIH1.
Papers relating to all three of these aspects have been submitted for review, or will be submitted in the next few months.