Individual
ESR projects

Research project

Uncovering alterations during hematopoietic differentiation in immune monogenic syndromes

Rationale and objectives

A subgroup of monogenic IEI patients is characterised by mutations in JAK-STAT signalling proteins, which comprise several kinases and transcription factors involved in inflammation. Gain-of-function (GOF) and loss-of-function (LOF) mutations are usually associated with life threatening immune dysregulation leading to an exacerbated inflammatory response and autoimmunity.

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1) To functionally characterise the germline variants in the JAK-STAT pathway (15-20 samples, both pediatric and adult) in steady state and following activation, using single cell omics approaches (scRNASeq, scATACseq)  on peripheral blood and biopsies.

2) To model JAK-STAT mutations by differentiating human induced pluripotent stem cells (hiPSC) carrying JAK-STAT mutations into multiple immune cell lineages.

3) To investigate the effects of different JAK-STAT inhibitors in the differentiation and cell-cell crosstalk using tools such as CellPhoneDB10  and in vitro modelling.

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Expected results

1) Identification of novel cell states in the  peripheral blood of patients carrying different JAK-STAT mutations.

2) Model JAK-STAT mutations during immune cell differentiation using hiPSCl.

3) Identification of the ability to revert epigenetic and transcriptomic changes by using specific drugs targeting the JAK-STAT pathway.

Planned secondments

UKLFR to receive training on various immunological methods, m10-m13 (3 months); Finally, DC12 will learn how to commercialise the output from his/her (epi)genetic findings by doing secondments at qGenomics (m26-m27 -1 month-) and EpiQMax (m27-m28 -1 month-).

PhD programme

PhD in Genomics, University of Cambridge, UK