Decoding the transcriptomic programs that define human macrophage function.

Macrophages are essential cells of the innate immune system, playing crucial roles in coordinating inflammatory responses and maintaining homeostasis. In cases of chronic inflammation, damaged tissues release abnormal signals that attract macrophages precursors to the local environment and drive macrophages toward a proinflammatory phenotype. This creates a feedback loop that sustains inflammation. The consequences to society are huge: chronic inflammatory diseases are among the leading causes of death and disability worldwide. Recent single-cell multi-omics studies have identified dysregulated macrophages as central players in chronic inflammation, but the molecular mechanisms sustaining these responses remain poorly understood.MACROCODE aims to unravel the molecular mechanisms governing the altered function of macrophages during chronic inflammation.The specific aims of this project are:1. Use CRISPR-Cas9 technology with single-cell read-outs to perturb genes in macrophages that show dysregulated expression between healthy and diseased states in chronic inflammatory conditions . Genes will be selected by creating an integrated single-cell transcriptomics atlas of macrophages in both health and disease. 2. Develop a computational framework using bioinformatics and AI tools to link these perturbed genes to transcriptomic programs, cellular functions and in vivo disease phenotypes.3. Validate key genes by modulating their expression using dCas9-VPR or KRAB systems, and evaluate the effects on macrophage differentiation, identity and function.Altogether, MACROCODE will decode the genetic regulation of macrophage dysfunction in chronic inflammation. This multidisciplinary project will equip me with advanced skills in genomics and bioinformatics, enhance my leadership and transferable skills, and prepare me for a future as an independent leader in the field of gene therapy for immune diseases.