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：
10678680
负责人：
Neal Dilip Amin
金额：
$ 22.88万
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/10678680
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 Mentors Messenger RNA MicroRNAs Modeling Motor Motor Neuron Disease Motor Neurons Mus Muscle Muscle Contraction Mutation Nervous System Neurologist Neuromuscular Junction Neuronal Dysfunction 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 Synapses System Therapeutic Tissues Training Universities Untranslated RNA Vertebral column bioinformatics pipeline career development comparative derepression design experience expression vector gene function gene network human model induced pluripotent stem cell insight motor control motor neuron degeneration 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.

项目概要/摘要在运动神经元疾病中，神经肌肉接头丢失并且运动神经元退化，导致 microRNA (miRNA) 的转录后基因调控进行性瘫痪和死亡。由于参与 miRNA 加工的蛋白质的遗传性突变，在运动神经元疾病中会受到破坏，然而，特定 miRNA 在人类运动神经元基因调控中的作用和我之前发现单个 miRNA，miR-218，是独特富集的。并且在小鼠运动神经元中大量表达。此外，缺乏 miR-218 的小鼠在运动神经元中表现出缺陷。神经肌肉突触发生并因肌肉麻痹而死亡——与运动神经元相关的表型随后的研究表明 miR-218 失调是运动神经元疾病的介质。然而，miR-218对靶基因通路的抑制与运动神经元之间的关系。表型尚未解决，并且 miR-218 的生物学作用之前尚未在人类，在我们对人类运动神经元基因调控的了解中留下了重要的翻译空白为了应对这一挑战，我们帕斯卡实验室最近开发了一种三维人类功能。诱导多能干（hiPS）细胞衍生的人类运动神经元发育和功能模型，称为阿明博士建议使用皮质运动组合体，通过融合皮质、脊髓和骨骼肌球体。这个新颖的系统可以模拟 miR-218 对运动神经元发育、靶标通路和人类的影响该提案将利用阿明博士现有的研究成果。精通运动神经元发育、miRNA 生物学和高级转录组学，并将实现新的与导师 Sergiu Pasca 博士一起接受干细胞生物学和人脑类器官模型的职业发展培训。阿明博士将利用斯坦福大学卓越的研究环境和资源。得到他的顾问委员会的支持，该委员会由非编码RNA介导的专家Howard Chang博士组成基因调控，运动神经元生物学和疾病途径专家 Aaron Gitler 博士和 Richard 博士雷默（Reimer）是一位执业神经学家和疾病发病机制专家，该提案的完成将为这一研究奠定基础。进一步研究 miR-218 及其靶标 mRNA 在人类运动中的治疗调节作用的方法神经元疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Motor neurons use push-pull signals to direct vascular remodeling critical for their connectivity.

运动神经元使用推拉信号来指导对其连接至关重要的血管重塑。

DOI：
发表时间：
2022-12-21
期刊：
影响因子：
16.2
作者：
Martins, Luis F;Brambilla, Ilaria;Motta, Alessia;de Pretis, Stefano;Bhat, Ganesh Parameshwar;Badaloni, Aurora;Malpighi, Chiara;Amin, Neal D;Imai, Fumiyasu;Almeida, Ramiro D;Yoshida, Yutaka;Pfaff, Samuel L;Bonanomi, Dario
通讯作者：
Bonanomi, Dario

Mouse embryo models built from stem cells take shape in a dish.

由干细胞构建的小鼠胚胎模型在培养皿中成型。