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MiR-218 regulatory networks in adult mice and its relationship to ALS

成年小鼠的 MiR-218 调控网络及其与 ALS 的关系

基本信息

批准号：
10196817
负责人：
SAMUEL L. PFAFF
金额：
$ 52.91万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196817
关键词：
ALS patients Adult Affect Alleles Amyotrophic Lateral Sclerosis Astrocytes Attenuated Automobile Driving Autophagocytosis Behavioral Birth Cell Nucleus Cells Cellular Stress Cessation of life Communities Complex Data Defect Development Disease Distal Down-Regulation Embryo Engineering Environment Extracellular Space Future Gene Expression Gene Mutation Genes Genetic Goals Grant Hand Strength Health Hindlimb Homeostasis Interneurons Intervention Light Link LoxP-flanked allele Maintenance Maps Mediating MicroRNAs Modeling Molecular Motor Motor Neuron Disease Motor Neurons Mus Muscular Atrophy Mutation Nerve Degeneration Neurodegenerative Disorders Neuromuscular Junction Nodal Pathway interactions Pattern Phenotype Play Proteins RNA metabolism Rare Diseases Reagent Research Risk Factors Role Sampling Specificity Spinal Spinal Muscular Atrophy Synapses Testing Therapeutic Therapeutic Agents Time Toxic effect Work amyotrophic lateral sclerosis therapy cell type cohort design disability early embryonic stage experimental study familial amyotrophic lateral sclerosis gene therapy motor control motor neuron degeneration mouse model neuromuscular neuron loss new therapeutic target next generation protein aggregation side effect spatiotemporal success therapeutic target transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (ALS) is a relatively-rare disease that leads to motor neuron degeneration in 1:50,000 people in the US. Since mutations in ~50 different genes have been linked to ALS, there is the daunting possibility that treatments will require the development of many separate therapies. Consequently, identification of the shared pathways and key nodal points affected in multiple forms of sporadic and familial ALS could provide greater impact for the overall ALS community. In this regard much effort is currently focused on pathways relevant to protein-stasis, autophagy and cell stress, since protein aggregates are a common feature of ALS. This proposal takes a complimentary approach by examining the mechanistic role played by an essential motor neuron-specific microRNA (miR-218) that is affected by ALS. Gene expression studies to identify microRNAs dysregulated in sporadic and familial ALS consistently detect downregulation of miR-218. A recent analysis of ALS patients found a cohort with mutations in miR-218, suggesting insufficient miR-218 levels/activity may be a risk factor for the disease. Because many ALS-linked genes affect RNA metabolism and microRNA processing complexes, it is hypothesized that miR-218 activity is downregulated in many types of ALS leading to a pattern of gene dysregulation that fails to sustain motor neurons. Conversely, it is predicted that ectopic miR-218 may restore proper gene expression in motor neurons and counteract ALS. While previous studies have established that miR-218 controls motor neuron connectivity in embryos, the goal of this grant is to identify the gene networks controlled by miR-218 in adult motor neurons using genetics to decrease (aim 1) and elevate (aim 2) miR-218 with precise spatiotemporal control. A floxed- miR-218 allele was created and following Cre-mediated deletion in adult motor neurons it was found that neuromuscular defects arose - indicating miR-218 is a critical regulatory molecule in mature motor neurons. In Aim 1 miR-218 will be conditionally deleted in adult mouse motor neurons and next generation RNA sequencing from single-nuclei will be used to (1a) uncover the miR-218 gene network in adult motor neurons, and (1b) cross- correlate miR-218-regulated genes with dysregulated genes in mouse models of ALS. In Aim 2, miR-218 will be conditionally (ectopically) expressed in mice to (2a) define non-cell-autonomous effects of mir-218, and (2b) model baseline levels of miR-218 in motor neurons that would be tolerable for potential ALS-therapies. These studies will pave the way for future experiments to directly test whether miR-218 can be used to attenuate ALS. To make this possible an independent but complementary R03 was submitted (see complimentary application) to allow others with ALS-models to explore this promising possibility with our miR-218 reagents. This R21 grant is an important step toward understanding the mechanism-of-action of miR-218 and how it might be used to attenuate ALS.

项目总结/文摘