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.
","abstract_html":"<p>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.</p>","abstract_has_math":false,"creators":["Koval, Erica Danielle"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Biology and Biomedical Sciences: Neurosciences","degree_department":null,"school":null,"contributors":["Timothy M Miller"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-09-01T07:00:00Z","date_published":"2014-09-01T07:00:00Z","updated_at":"2026-07-24T06:13:40Z","subjects":["ALS","inflammation","microRNA","neurodegenerative"],"languages":["English (en)"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.7936/K73T9F7C"],"render_values":[{"text":"https://doi.org/10.7936/K73T9F7C","href":"https://doi.org/10.7936/K73T9F7C","code":true}]}]},"links":{"outbound_url":"https://openscholarship.wustl.edu/etd/1313","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Timothy M Miller"]},{"key":"dc:creator","label":"Author","values":["Koval, Erica Danielle"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2016-10-07T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biology and Biomedical Sciences: Neurosciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["ALS","inflammation","microRNA","neurodegenerative"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English (en)"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://openscholarship.wustl.edu/etd/1313"]},{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.7936/K73T9F7C"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["MicroRNAs in ALS: Defining Cell-Type Specific Expression, Developing Methods to Modulate MicroRNAs in vivo, and Identifying Novel Therapeutic Targets"]}]}],"canonical_facts":{"dc:contributor":["Timothy M Miller"],"dc:creator":["Koval, Erica Danielle"],"dc:date.available":["2016-10-07T07:00:00Z"],"dc:description.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.
"],"dc:identifier":["https://openscholarship.wustl.edu/etd/1313"],"dc:identifier.doi":["https://doi.org/10.7936/K73T9F7C"],"dc:language":["English (en)"],"dc:subject":["ALS","inflammation","microRNA","neurodegenerative"],"dc:title":["MicroRNAs in ALS: Defining Cell-Type Specific Expression, Developing Methods to Modulate MicroRNAs in vivo, and Identifying Novel Therapeutic Targets"],"thesis:degree_discipline":["Biology and Biomedical Sciences: Neurosciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T06:13:40Z"}