Chemistry and Chemical Biology ETDs

Publication Date

Summer 7-18-2018

Abstract

MicroRNAs (miRNAs) are short (~ 22 nucleotides long) noncoding RNAs that regulate gene expression post-transcriptionally. They control the expression of various genes that are crucial for cellular function, development and human diseases. Tools to regulate the level and function of miRNAs facilitate the studies of their functions and have therapeutic applications. In my thesis, I developed a newly customizable miRNA biogenesis inhibitor to regulate miRNAs.

Antisense oligonucleotides (ASOs) have been used to regulate miRNA through controlling their production or function. Although commonly used due to the fact that they are easy to design, several limitations exist for ASOs including serious off-target effects, low cellular permeability and poor pharmacokinetics and distribution. To address these limitations, we proposed a new class of ASO based bi-functional molecules using short ASOs as the pre-miRNA recognition unit linked to an RNase III inhibitor as a Dicer inhibitor to block miRNA maturation. We showed the feasibility of the bi-functional strategy and optimized the bi-functional molecules by enhancing each functional unit as compounds 12, 22 and 25. Additionally, we identified cell penetrating peptide (CPP) that facilitate the delivery of bi-functional molecules to address the cell permeability issue.

We also explored the feasibility of using cyclic peptidomimetics as an alternative class of molecule to target RNAs, which can be used as our pre-miRNA recognition unit in the bi-functional regulator. We identified a new pre-miR-155 binder (compound 27) that inhibits miR-155 biogenesis. Applying RNAseq and bioinformatics analysis, we investigated its targeting selectivity and downstream effects.

Language

English

Keywords

microRNA, miRNA regulation, Dicer inhibition

Document Type

Dissertation

Degree Name

Chemistry

Level of Degree

Doctoral

Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Fu-Sen Liang

Second Committee Member

Nora Perrone-Bizzozero

Third Committee Member

Jeremy Edwards

Fourth Committee Member

Wei Wang

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