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Research areas
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Identification of novel RNA editing/RNA modification events in RNA
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Investigating the biological function of nucleotide modification in innate immunity
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Elucidating the role RNA modification in disease
Main objectives
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To define the prevalence and biological function of RNA modification in RNA.
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To establish in vitro systems whereby the level of different RNA modification can be altered so that the global consequences can be studied.
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To determine if there are alterations in RNA modifications in autoimmune disorders.
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To investigate if ADAR2 has a role in innate immunity in the brain.
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Content of research
Innate immunity and inflammation are central to human health. This was stated succinctly by the Nobel Laureate David Baltimore in 2011: ‘Autoimmunity, cancer and metabolic diseases are all secondary to chronic inflammation. This places inflammation at the heart of modern medicine’. The ‘Damage Model’ of Polly Matzinger proposes that innate immunity does not response to pathogens but responds to danger as defined by cellular damage. Therefore different cellular stresses can cause cellular damage, accidently triggering innate immunity which manifests itself as an autoimmune disease.
For many years my group has studied ADARs that convert adenosine to inosine in dsRNA. In 2014 we were the first to demonstrate that inosine in cellular RNA allows the cell to discriminate between self and non-self RNAs. We showed that the Adar1-/-embryo is dead by day E12.5 as it lacks hematopoietic progenitor cells and has elevated interferon levels. However this mutant can be rescued by a mutation in Mavs-/- demonstrating that Adar1 is an essential component of the innate immune pathway.
There are over 140 different types of RNA modification so we propose that RNA modifications other that inosine play a role in the innate immune response. Therefore we want to isolate and identify different classes of RNAs (not tRNAs and rRNAs) which are enriched in RNA modification, investigate their biological functions if their levels change in autoimmune disorders.
