Poster Presentation 43rd Lorne Genome Conference 2022

Programmable macrophages understanding the role of nrg1 and macrophage plasticity through synthetic biology (#128)

Miguel A Berrocal-Rubio 1 , Ricardo De Paoli-Iseppi 1 , Michael Clark 1 , Daniel Heath 1 , Christine Wells 1
  1. University of Melbourne, CARLTON, VIC, Australia

Neuregulin-1 (NRG1) is a pleiotropic growth factor that signals via EGF receptors. It is essential for healthy organ development, cell maturation and metabolism, with defined roles in the heart, skeletal muscle, neurons and the gut. NRG1 belongs to a complex family of transmembrane proteins that are regulated transcriptionally through differential use of promoters and alternative exon splicing, and post-transcriptionally via enzymatic processing of propeptides. This structural complexity makes it hard to discern how NRG1 functions in different tissues, and constitutive loss is lethal in rodent knock-out models. We hypothesize that NRG1 is one of the missing links in in vitro developmental protocols of multicellular organoids. Through nanopore long-read sequencing, we have been able to identify and sequence the NRG1 isoforms expressed in human macrophages, which include a myeloid specific isoform that was previously uncharacterised. Applying principles of synthetic biology and genetic engineering to stem-cell derived macrophages, we aim to design a model in which we can track and control NRG1 signalling. This system will allow better understanding of NRG1 dynamics, the influence of its signal in the receiving cell, and the processes that happen prior to its expression in the signalling cell.  Developing a macrophage with a controllable and trackable synthetic NRG1 would enable deeper understanding of macrophage roles during organogenesis, as well as deeper understanding of the functions of NRG1 in development and disease processes.