ESR projects

Research project

Understanding the functional & epigenetic impact of NF-kB mutants in dendritic cell/macrophage differentiation

Rationale and Objectives

Mutations in different transcription factors and cell signalling molecules account for a significant proportion of IEI. Defects in NF-κB activation lead to a broad range of developmental manifestations and infections due to impaired signalling pathways downstream of both innate and adaptive immune system receptors. DC1’s project will focus on the analysis of the impact in the immunological properties in relation to the epigenomic and transcriptomic changes related to altered immune responses in different cell types during differentiation and activation in individuals carrying different NF-kB pathway mutations.

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1) To characterize the impact of selected mutations related to the NF-kB pathway in the ability to differentiate and activate dendritic cells/macrophages derived from monocytes, monitored by flow cytometry, ELISA, etc.

2) To profile DNA methylation, selected histone modifications, transcriptome and cytokine profiling in monocytes differentiated to dendritic cells/macrophages carrying NF-kB-pathway mutations. Characterization of the interplay between TFs and epigenetic enzymes.

3) To genetic and pharmacologically modulate the immunogenic properties of monocyte-derived dendritic cells isolated from patients with different NF-kB-pathway mutations and determine the impact on epigenomic and transcriptomic profiles.

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Expected results

1) Determination of the impact of the differentiation and immune properties of dendritic cells derived from monocytes carrying different NF-kB pathway mutations.

2) Elucidation of the epigenetic and transcriptional effects during differentiation and activation of dendritic cells derived from monocytes carrying different NF-kB pathway mutations.

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

Planned secondments

CCI (Grimbacher) to receive training on various immunological methods, m10-m13 (3 months); GRL (Vento-Tormo) to receive training on standards for single-cell omics analysis methods, m15-m18 (1 month); IRB (Geiger) to receive training on gene editing, m21-m24 (3 months). Finally, DC1 will learn how to convert the output from his/her findings into epigenetic detection kits by doing a secondment at EpiQMax. m26-m28 (2 months)

PhD programme

PhD in Biomedicine, University of Barcelona (UB), Spain