MicroRNAs represent a large class of non-coding RNAs that regulate gene expression by interacting with the 3'-untranslated region of target mRNAs. In addition to being essential regulators of development, differentiation and many other basic cellular processes, microRNA expression is associated with the progression of cancer and other chronic diseases, suggesting that regulation of specific microRNAs could have significant therapeutic benefits. Our objective is to investigate the mechanism by which pre-mRNA splicing factors regulate processing of a subset of miRNA precursors. Since we have also identified peptide mimetics that inhibit processing of an oncogenic miRNA (miR- 21) by the RNase III enzyme Dicer, we also propose to investigate the mechanism of inhibition of microRNA processing by this new class of molecules and to further develop their activity. We specifically propose to: 1) Study the regulation of microRNA processing by the Fox-1 family of splicing factors. We will investigate the structural and biochemical mechanism of regulation and the physiological consequences of downregulation of miR-20b expression by Fox-1 and Fox-2. 2) Study the structural and biochemical mechanism of inhibition of microRNA processing by a new class of peptide mimetics and by engineered RNA- binding proteins we have identified. 3) Improve the activity of the peptide inhibitors we have discovered. By conducting this project, we will investigate how processing of microRNA precursors is regulated by endogenous RNA-binding proteins and by exogenous inhibitors. This will provide information critical to understand post-transcriptional regulation of microRNA production, and new approach to inhibiting the activity of oncogenic microRNAs and to improve the potency of the inhibitors.

Public Health Relevance

This project aims to investigate how individual microRNAs are post-transcriptionally regulated, to clarify an essential biological process critical to the regulaion of a majority of eukaryotic genes, and to provide information needed for the discovery of new inhibitors of specific microRNAs overexpressed in cancer or other chronic diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01GM103834-01A1
Application #
8630834
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Preusch, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195