Biogenesis of Oncogenic MicroRNAs : from the structure of the microRNA processing complexes to the inhibition of the maturation of human oncogenes

Objective

Micro-RNAs are a recently identified class of small non-coding RNAs that have been shown to regulate the expression of up to 30% of human genes. The contribution of miRNAs in gene regulation is gaining considerable attention, particularly given the growing links between miRNA mis-function or expression and disease. Certain miRNAs have been demonstrated to display oncogenic-like phenotypic effects and their overexpression is heavily implicated in the development of cancers. MiRNAs mature via a two-step pathway involving two processing complexes: first Drosha-DCGR8 and second Dicer-PACT-TRBP. The two ribonucleases Drosha and Dicer are recruited by multi-domain RNA-binding accessory proteins that interact with specific, but currently unknown, structural features present in immature miRNAs. In this project I propose to perform an ambitious and comprehensive multidisciplinary analysis of biomolecular interaction networks involved in human miRNA biogenesis. An automated molecular biology approach will be employed to rapidly clone, express and screen soluble domains derived from each modular processing protein. I will use the latest fast NMR methods to rapidly assess protein and RNA folds, and protein and RNA interaction sites. These results will define the roles of each biogenesis protein, describe RNA recognition mechanisms and reveal the first atomic resolution picture of miRNA processing complexes. This structural evaluation will form the basis for the design and testing of inhibitors of miRNA biogenesis. Over-expression of oncogenic miRNAs correlates well with cancer. I propose to evaluate the possibility of using anti-sense oligonucleotides to block the regions of the immature miRNA recognized by the biogenesis machinery. The efficacy of these molecules will be explored in vivo with the view to developing innovative ways of probing miRNA function or potential new cancer therapies.

Fields of science (EuroSciVoc)

CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.

• natural sciences biological sciences biochemistry biomolecules proteins
• medical and health sciences clinical medicine oncology
• natural sciences biological sciences genetics RNA
• natural sciences biological sciences molecular biology

Keywords

Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)

• Biochemistry
• Biophysics
• NMR spectroscopy
• Structural Biology
• biogenesis
• cancer
• micro-RNA
• oncogenes

Programme(s)

Multi-annual funding programmes that define the EU’s priorities for research and innovation.

• FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Topic(s)

Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.

• FP7-PEOPLE-IRG-2008 - Marie Curie Action: "International Reintegration Grants"

Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

FP7-PEOPLE-IRG-2008
See other projects for this call

Funding Scheme

Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.

MC-IRG - International Re-integration Grants (IRG)

Coordinator