Objective
microRNA-34a (miR-34a) is mis-regulated in ~75% of cancers and is considered a promising drug target. In a recent clinical trial, miR-34a was used against terminal liver cancer showing promising result with remission of 3 patients. However, mortality remained high and was attributed to its ability to target multiple mRNAs. Project ECONOMICS will investigate this issue by elucidating the underlying structure and dynamics of multiple miR-34a:mRNA complexes using NMR spectroscopy and molecular dynamic simulations. This will provide information about the conformation of miR-34a which is mRNA specific. This can further be stabilized by mutations to increase target specificity of miR-34a leading to an improvement in clinical trial results. miR-34a targets and binds the 3’-untranslated-region (3’-UTR) of ~100 mRNAs via the RNA-induced silencing complex, resulting in downregulation of the associated genes. Recently, it was discovered that miR-34a attains a high energy excited state (ES) conformation for mRNA encoding gene SIRT1. Stabilizing this ES resulted in a two-fold increase in gene repression. Can miR-34a have a similar ES for other genes implicated in various cancers? This will be studied by exploring the structure and dynamics of miR-34a when complexed with 3’-UTR of the mRNA encoding the genes HNF4a, NOTCH1, NOTCH2, DLL1 and WNT1. Cellular environment is proposed to affect the ES of miR-34a, therefore a detailed conformational landscape of miR-34a:mRNA complexes will be mapped by comparing both in vitro and in live human cells (cancerous and non-cancerous). This study will provide targeting rules for microRNA within the cell and insight into its regulatory mechanism. This information will improve the efficiency RNA based drug development, giving a competitive edge to EU’s pharmaceutical industry, and ultimately realizing “Europe’s Beating Cancer plan” to achieve long-term survival of 70% patients with cancer by 2035.
Fields of science
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health sciencesclinical medicineoncologyliver cancer
- social sciencessociologydemographymortality
- natural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopy
- natural sciencesbiological sciencesgeneticsRNA
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
751 05 Uppsala
Sweden