Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Neurosciences

Language

English (en)

Date of Award

Summer 9-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Timothy M Miller

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neuromuscular disease with no adequate therapies. MicroRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS model SOD1G93A rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. Generation of mice that express a GFP-tagged miRNA processing protein behind cell-type specific promoters allowed for the identification of miRNA expression patterns in various neural cell types. From this information, we focused on the role of miR-155 on glial cells and particularly on neuroinflammatory pathways in ALS. miR-155, miR-146a, and miR-142-5p were upregulated beginning in a mid-disease stage and were highly correlated with one another and with various neuroinflammatory mediators. To test miRNA inhibition in the central nervous system as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the central nervous system and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1G93A mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS.

DOI

https://doi.org/10.7936/K73T9F7C

Comments

This work is not available online per the author’s request. For access information, please contact digital@wumail.wustl.edu or visit http://digital.wustl.edu/publish/etd-search.html.

Permanent URL: http://dx.doi.org/10.7936/K73T9F7C

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