Inflammation, essential component of the innate immune response, allows multicellular organisms to repair damaged tissue. Excessive inflammation however, can itself exacerbate tissue damage, leading to chronic inflammation-related disease. The expression of crucial mediators of the inflammatory response is tightly regulated at transcriptional and post-transcriptional levels. Recent studies have shed some light on how cytoplasmic RNA processing events regulate mRNAs encoding inflammation mediators. However, it is unknown how nuclear post-transcriptional events control the expression of such molecules and what the contribution of RNA binding proteins (RBPs) in this control is.
An RBP that has emerged as a pleiotropic modulator of mRNA function is HuR (Human antigen R) protein. In the cytoplasm, HuR stabilises many mRNAs via interplay with other RBPs. Research from the host laboratory has shown that over-expressed HuR represses translation of specific inflammatory mRNAs and attenuates acute inflammatory reactions, an unexpected role for HuR given its previous characterisation as an mRNA stabiliser. However, the role of HuR in the nucleus, where is most abundant, is still not understood. What is known is that nuclear HuR interacts, in an RNA dependent manner, with certain hnRNPs known to play a role in post-transcriptional regulation of gene expression. However, the role of these nuclear HuR-hnRNP interactions is unclear.
The proposed research aims to understand the role of the nuclear HuR-hnRNP complexes in post-transcriptional regulation of inflammatory response in mouse macrophages. The Researcher’s expertise in studying ribonucleoprotein interactions in RNA function and processing in vitro will be combined with the Supervisor’s in functional study of post-transcriptional regulators in vivo and ex vivo. We will characterise the nuclear HuR-hnRNP complexes at both protein and RNA levels, and study their biological functions in regulating inflammatory gene expression.
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