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In cellular conformations of microRNA-34a via magnetic resonance

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... see more

31/12/2024

207K€

Project Budget: 207K€

Project leader

UPPSALA UNIVERSITET No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

PARTICIPATION DEPralty Sin fecha límite de participación.

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Financing granted El organismo HORIZON EUROPE notifico la concesión del proyecto The day 2024-12-31

HORIZON-MSCA-2021-PF-01-01: MSCA Postdoctoral Fellowships 2024 ExpectedOutcome:

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Cerrada does 9 months

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Este proyecto no cuenta con búsquedas de partenariado abiertas en este momento.

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2 Participantes

172.41K€ | Leader

34.48K€ | participant

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Project duration: 30 months Date Start: 2022-06-09
End date: 2024-12-31

Project leader

UPPSALA UNIVERSITET No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Project Budget 207K€

participation deadline Sin fecha límite de participación.

Project description 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.

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