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: 10650146
• 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/10650146
• 关键词: Alzheimer' s disease model; Animal Behavior; Animals; Astrocytes; Base Pairing; Behavioral; Behavioral Assay; Brain; Brain Injuries; Bypass; Cells; Clinical Trials; Cues; Disease; Environment; Ethical Issues; Exhibits; Foundations; Future; Gene Expression; Gene Expression Profile; Genes; Glutamates; Goals; In Situ; Injury; Knock-out; Laboratories; Mediating; MicroRNAs; Modeling; Molecular; Neuroglia; Neurons; Nucleotides; Penetration; Phenotype; Play; Process; Recovery; Recovery of Function; Regenerative Medicine; Research; Role; Signal Pathway; Slice; Small RNA; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Stem cell transplant; Technology; Therapeutic; Tissues; Transcription Coactivator; Untranslated RNA; cell replacement therapy; chemical synthesis; experience; improved; in vivo; innovative technologies; miRNA expression profiling; mouse model; nervous system disorder; neurodevelopment; neuronal circuitry; novel therapeutics; overexpression; programs; 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。 损伤和恢复局部神经元回路以进行功能修复。干细胞移植疗法曾显示 伟大的承诺。然而，其疗效在临床试验、免疫排斥和伦理问题中并不令人满意 仍然存在问题。体内重编程正在成为再生免疫学的一个潜在的新突破。 药这项创新技术字面上将内源性神经胶质细胞转化为功能性神经元进行修复 目的，绕过干细胞替代疗法面临的挑战性问题。先前 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 通过过表达一种抗阿尔茨海默病的药物， 单转录因子NeuroD 1（Guo et al，2014; BEST of 2014 Article in Cell Stem Cell）。然而，分子 重编程过程的机制仍然难以捉摸。microRNAs（miRNAs）是一类小的非编码RNA 在神经发育和疾病中起着关键作用。miRNAs的功能可能是广泛的， 鉴于一个miRNA可以通过独特的不完全碱基配对机制调节许多靶基因， 对细胞中的基因表达谱产生全局影响。在本提案中，PI将结合联合收割机的专业知识 在SCI和miRNA上，并在小鼠中检查NeuroD 1介导的神经元转换期间miRNA的功能。 SCI模型该建议的中心假设是，miRNAs在神经元细胞凋亡过程中发挥重要作用。 重新编程过程，并且miRNAs的强制表达，以及NeuroD 1，可以重新编程反应性 星形胶质细胞转化为神经元用于SCI后的功能修复。PI提出了三个具体目标：1）确定 miRNA在损伤脊髓中NeuroD 1介导的神经元转化过程中的功能; 2）确定 SCI后通过miRNAs将反应性星形胶质细胞转化为神经元; 3）为了确定 脊髓损伤后miRNA转化的神经元及其对动物行为的影响完成本提案 将显示miRNA介导的胶质细胞向神经元转化的可行性，并为治疗奠定基础。 这种小RNA分子在未来作为合成药物的应用。PI认为，该提案将 从而为SCI以及其他神经系统疾病提供了新治疗方法。