C2D2 Research 3a - Small molecule manipulation of microRNA biogenesis: application to microRNAs linked to chronic diseases

Project: Other projectOther internal award

Project Details

Layman's description

Access to the information stored in our genomes is tightly controlled. One recently identified regulatory mechanism involves RNA, a versatile biological polymer related to DNA . Cells can produce small RNA molecules that can ‘interfere’ with physiological processes by controlling the production of effector proteins. Numerous regulatory RNA molecules (called microRNAs due to their small size) have been identified in humans and they have been linked to fundamental biological processes such as development, proliferation, differentiation and cell death. Their central importance is highlighted by the fact that many microRNAs are implicated in cancers.

Cells synthesize each microRNA using the same machinery. A great deal is known about microRNA biogenesis, but many critical questions remain unanswered. We aim to determine the common and unique themes underpinning microRNAs synthesis. This information will drive the design of molecules that inhibit the biosynthesis of microRNAs implicated in cancers and other diseases. In this preliminary study, we propose to implement a recently reported method for producing samples of microRNAs. This technique will greatly enhance our ability to characterise and manipulate microRNA function. Using this approach we will produce samples of disease-related microRNAs for use in the hunt for small molecules that selectively control their synthesis.

Key findings

A primary goal for this project was to utilise a new-to-York approach for generating milligramme quantities of pure RNA samples for biophysical analysis and interaction studies. This goal was achieved and we have successful implemented the described approach to produce milligramme quantities of samples of precursor microRNAs. These samples are currently being channeled into a variety of structural biology and ligand binding studies.

The output of this project directly underpins a PhD studentship (2014-17), which is funded as part of a White Rose doctoral train programme on RNA/ligand interactions. The recruited PhD student is co-supverised in a new collaboration between the PI and Prof Mike Williamson (U. Sheffield).
This project supported a new collaboration between the PI and Drs Carine Tisné and Luc Ponchon, Université Paris Descartes, France.
This work also provided the platform for a wider collaboration network including colleagues from the Centre for Immunology and Infection, Departments of Chemistry and Biology and York Structural Biology Laboratory.

This project included funding for 8 months of technical support from Mike Hodgkinson.

Technical skills acquired in this project were used to support application to Technology Strategy Board (see below) for collaboration with Quorn

Technology Strategy Board (£165,931; Submitted: Feb 2015)

C2D2 Early Career Fellowship (£99,619; Feb 2015 - Jan 2017)

BBSRC New Investigator Award (April 2014).
British Council Newton Fund UK/Egypt International Links Award (Nov 2014)
Effective start/end date1/02/1431/12/14