Mapping the cellular network that regulates immunogenicity of self nucleic acids
This project aims to map the protein and gene networks that regulate the immunogenicity of the cells own RNA. It is essential that cells can tell the difference between nucleic acids, both RNA and DNA, that are made by the cell and so not a threat compared to nucleic acids derived from pathogens such as viruses that invade the cell. We know that when this process goes wrong it can have deadly consequences, exemplified by Aicardi-Goutieres Syndrome (AGS) and autoimmunity.
We have determined that a specific RNA modification termed Adenosine-to-Inosine (A-to-I) editing is a key regulator of the cells ability to discriminate “self” from “non-self” RNA. A-to-I editing is mediated by ADAR enzymes, with ADAR1 activity critical for this immune sensing pathway. We will use genome-wide screens and functional genomics to define the depth and breadth of the cellular network that can regulate the immunogenicity of the cells own RNA. We will use saturation mutagenesis to understand how these proteins interact and modulate immunogenicity of self RNA. This will be key to understanding how the innate immune system detects RNA and how we can promote or suppress this response.
We use mouse models, cell culture, molecular and biochemical techniques to model loss of editing by ADAR1 to better understand how cells deal with their own dsRNA. This project would characterize new players in this pathway identified in a genome-wide CRISPR/Cas9 screen.
Techniques – RNA biology, genetics, cell culture, molecular biology, biochemistry, CRISPR/Cas9, genome-wide screening, bioinformatics
Dr Jacki Heraud-Farlow
Prof Carl Walkley
Cancer & RNA biology
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