MicroRNA Function During Neuronal Reprogramming in Treating Spinal Cord Injury

MicroRNA 在治疗脊髓损伤的神经元重编程过程中的功能

• 批准号: 10461769
• 负责人: HEDONG LI
• 金额: $ 36.19万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461769
• 关键词: Alzheimer' s disease model; Animal Behavior; Animals; Astrocytes; Base Pairing; Behavioral; Behavioral Assay; Brain; Brain Injuries; Bypass; Cells; Chemicals; Clinical Trials; Cues; Disease; Environment; Ethical Issues; Exhibits; Foundations; Future; Gene Expression; Gene Expression Profile; Genes; Glutamates; Goals; In Situ; Injury; Instruction; Knock-out; Laboratories; Lead; Mediating; MicroRNAs; Modeling; Molecular; Neuroglia; Neurons; Nucleotides; Phenotype; Play; Process; Recovery; Recovery of Function; Regenerative Medicine; Research; Role; Signal Pathway; Slice; Small RNA; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Spinal cord injury patients; Stem cell transplant; Technology; Therapeutic; Tissues; Transcription Coactivator; Untranslated RNA; cell replacement therapy; experience; improved; in vivo; innovative technologies; miRNA expression profiling; mouse model; nervous system disorder; neurodevelopment; neuronal circuitry; novel therapeutics; overexpression; reconstruction; repaired; spinal cord repair; stem cell replacement; stem cells; synthetic drug; transcription factor; transcriptome sequencing; transplantation therapy

Project Summary: One major obstacle in treating spinal cord injury (SCI) is to replenish neurons that are lost during the course of injury and to restore local neuronal circuitry for functional repair. Stem cell transplantation therapy once showed great promise. However, its efficacy has not been satisfactory in clinical trials; immunorejection and ethical issues remain problematic. In vivo reprogramming is emerging as a potentially new breakthrough in regenerative medicine. This innovative technology literally converts endogenous glial cells into functional neurons for repair purposes, bypassing the challenging questions that stem cell replacement therapies are facing. Previous research from the PI’s lab has demonstrated that reactive astrocytes can be successfully converted in situ into functional neurons in both injured brain and brain of a model for Alzheimer’s disease by overexpression of a single transcription factor NeuroD1 (Guo et al, 2014; BEST of 2014 Article in Cell Stem Cell). However, molecular mechanisms of the reprogramming process remain elusive. MicroRNAs (miRNAs) are small non-coding RNAs that play pivotal roles during neural development and diseases. The function of miRNAs could be extensive given that one miRNA may regulate many target genes through the unique imperfect base-pairing mechanism exerting a global impact on the gene expression profile in a cell. In this proposal, the PI will combine his expertise on SCI and miRNA, and examine miRNA function during NeuroD1-mediated neuronal conversion in a mouse model of SCI. The central hypothesis of this proposal is that miRNAs play essential roles during the neuronal reprogramming process, and that forced expression of miRNAs, as well as NeuroD1, can reprogram reactive astrocytes into neurons for functional repair after SCI. The PI proposes three specific aims: 1) To determine miRNA function during NeuroD1-mediated neuronal conversion in the injured spinal cord; 2) To determine conversion of reactive astrocytes into neurons by miRNAs after SCI; 3) To determine functional integration of miRNA-converted neurons and their effects on animal’s behavior after contusive SCI. Completion of this proposal will show feasibility of miRNA-mediated glia-to-neuron conversion and lay out foundation for therapeutic application of this small RNA molecule as a synthetic drug in the future. The PI believes that this proposal will lead to a novel therapeutic treatment for SCI as well as other neurological disorders.

项目概要： 治疗脊髓损伤（SCI）的一个主要障碍是补充在脊髓损伤过程中丢失的神经元。 一旦显示出干细胞移植疗法可以修复损伤并恢复局部神经元回路。 然而，其疗效在临床试验中并不令人满意，并且存在伦理问题。 体内重编程正在成为再生领域潜在的新突破。 这项创新技术实际上将内源性神经胶质细胞转化为功能性神经元以进行修复。 目的，绕过干细胞替代疗法面临的挑战性问题。 PI 实验室的研究表明，反应性星形胶质细胞可以成功地原位转化为 通过过度表达a，在受伤的大脑和阿尔茨海默病模型的大脑中发现功能神经元 单一转录因子 NeuroD1（Guo 等人，2014 年；Cell Stem Cell 2014 年最佳文章）。 重编程过程的机制仍然难以捉摸。MicroRNA (miRNA) 是小型非编码 RNA。 在神经发育和疾病中发挥关键作用 miRNA 的功能可能很广泛。 鉴于一个 miRNA 可以通过独特的不完美碱基配对机制调节许多靶基因 在这项提案中，PI 将结合他的专业知识对细胞中的基因表达谱产生全局影响。 SCI 和 miRNA 的研究，并检查 NeuroD1 介导的小鼠神经元转换过程中 miRNA 的功能 该提案的中心假设是 miRNA 在神经元过程中发挥重要作用。 重编程过程，强制表达 miRNA 以及 NeuroD1，可以重编程反应性 SCI 后将星形胶质细胞转化为神经元进行功能修复。PI 提出了三个具体目标：1) 确定 受损脊髓中 NeuroD1 介导的神经元转换过程中的 miRNA 功能； SCI 后反应性星形胶质细胞通过 miRNA 转化为神经元；3) 确定星形胶质细胞的功能整合； miRNA 转化的神经元及其对挫伤性 SCI 后动物行为的影响 完成本提案。 将展示 miRNA 介导的胶质细胞到神经元转化的可行性，并为治疗奠定基础 PI相信该提案将在未来将这种小RNA分子用作合成药物。 导致 SCI 以及其他神经系统疾病的新型治疗方法。