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Modulating miR-218 in human motor neurons using assembloids

使用组合体调节人类运动神经元中的 miR-218

基本信息

批准号：
10525638
负责人：
Neal Dilip Amin
金额：
$ 19.52万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-08 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525638
关键词：
3&apos Untranslated Regions 3-Dimensional ALS patients Advisory Committees Antibodies Autocrine Communication Autopsy Award Axon Bioinformatics Biological Biological Assay Biological Process Biology Brain CRISPR/Cas technology Cessation of life DNA Sequence Alteration Defect Development Disease Disease Pathway Dose Environment Evolution Exhibits Functional disorder Future Gene Expression Gene Expression Regulation Genes Glutamates Goals Histology Human Image Inherited Investigation Knowledge Ligands Mediating Mediator of activation protein Mentors Messenger RNA MicroRNAs Modeling Motor Motor Neuron Disease Motor Neurons Mus Muscle Muscle Contraction Mutation Nervous system structure Neurologist Neuromuscular Junction Neurons Organoids Paralysed Pathogenesis Pathway interactions Phenotype Post-Transcriptional Regulation Proteins Regulation Regulator Genes Regulatory Pathway Reporter Repression Research Resources Role Scientist Skeletal Muscle Spinal Sum Synapses System Therapeutic Tissues Training Universities Untranslated RNA base bioinformatics pipeline career development comparative design experience expression vector gene function gene network human model induced pluripotent stem cell insight motor control motor neuron development motor neuron function mouse genetics neurodevelopment neuromuscular neuromuscular function novel optogenetics overexpression predictive modeling presynaptic protein TDP-43 receptor response skills stem cell biology stem cell model synaptogenesis transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT In motor neuron diseases, neuromuscular junctions are lost and motor neurons degenerate resulting in progressive paralysis and death. Post-transcriptional gene regulation by microRNAs (miRNAs) is hypothesized to be disrupted in motor neuron diseases due to inherited mutations in proteins involved in miRNA processing, such as TDP43, FUS, and SMN. Yet, the role of specific miRNAs in human motor neuron gene regulation and function is not well characterized. I previously discovered that a single miRNA, miR-218, is uniquely enriched and abundantly expressed in mouse motor neurons. Furthermore, mice lacking miR-218 exhibited deficits in neuromuscular synaptogenesis and die due to muscle paralysis – phenotypes associated with motor neuron disease. Subsequent studies have implicated miR-218 dysregulation as a mediator of motor neuron disease in humans. However, the relationship between miR-218’s repression of target gene pathways and motor neuron phenotypes has not been resolved, and the biological role of miR-218 has not been previously investigated in humans, leaving an important translational gap in our knowledge of human motor neuron gene regulation and function. In response to this challenge, we in the Pasca Lab have recently developed a three-dimensional, human induced pluripotent stem (hiPS) cell-derived model of human motor neuron development and function, called cortico-motor assembloids, by fusing cortical, spinal, and skeletal muscle spheroids. Dr. Amin proposes using this novel system to model the impact of miR-218 upon motor neuron development, target pathways, and human specific-features of post-transcriptional gene regulation. This proposal will leverage Dr. Amin’s existing proficiencies in motor neuron development, miRNA biology, and advanced transcriptomics and will enable new career development training in stem cell biology and human brain organoid models with mentor Dr. Sergiu Pasca. Dr. Amin will utilize the exceptional research environment and resources available at Stanford University. He will be supported by his advisory committee comprising of Dr. Howard Chang, an expert in non-coding RNA mediated gene regulation, Dr. Aaron Gitler, an expert in motor neuron biology and disease pathways, and Dr. Richard Reimer, a practicing neurologist and expert in disease pathogenesis. Completion of this proposal will pave the way for further investigations into the therapeutic modulation of miR-218 and its target mRNAs in human motor neuron disease.

项目总结/文摘