Consequences of inflammatory activation of RNA decay pathways for cell-fate in vitro and in vivo
Navn på bevillingshaver
Seyed Mojtaba Ghiasi
Institution
University of Copenhagen
Beløb
DKK 583,000
År
2018
Bevillingstype
Reintegration Fellowships
Hvad?
Normal cellular function depends on balanced transcription of DNA to RNA and translation of RNA to protein. Since there is no RNA repair system, defective RNA is degraded via the so-called no-go decay and nonsense-mediated decay pathways. Inflammation is known to alter gene transcription. In addition, I recently discovered that inflammation activates RNA degradation in insulin-producing beta cells, but the mechanism and functional consequences remains to be elucidated. Therefore, this project aims to understand the mechanisms of inflammatory activation of RNA decay pathways, their implications for cellular function and viability in cell- and animal-models and whether genetic variation in RNA decay pathways confers risk of diabetes in humans.
Hvorfor?
Clarifying the regulation of RNA decay is of fundamental importance to understand how the cell accommodates to the conditions of the 'central dogma': that DNA is transcribed to RNA which is translated to protein. Describing the mechanisms and implications of inflammatory regulation of RNA decay in mammalian cells will add important basic physiological and pathophysiological information needed for ensuing identification of clinically relevant targets and guide development of novel treatments of disorders associated with acute or chronic inflammation.
Hvordan?
I will investigate if inflammatory insults lead to RNA damage in beta-cells, chosen as a model-cell because of its high insulin mRNA and protein turnover and high pro-inflammatory cytokine receptor expression. Using high-throughput RNA sequencing and ribosomal profiling I will examine how knock-down of key RNA decay components will modify beta-cell transcriptomic changes in response to inflammatory insult. Advanced bioinformatics will clarify differential actions of the targeted RNA decay pathways on beta-cell secretory function and viability. The impact of knocking-out RNA decay components on the metabolic phenotype will be tested in high-fat fed transgenic mice. Finally, the diabetes risk conferred by genetic variations in RNA decay will be studied in humans.