Motor Neuron Regeneration Model on ALS-Like Mouse Lifes*

ALS 样小鼠的运动神经元再生模型*

• 批准号: 6780821
• 负责人: RUGAO LIU
• 金额: $ 0.13万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2004-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780821
• 关键词: amyotrophic lateral sclerosis; biomarker; cell differentiation; gene expression; gene induction /repression; genetically modified animals; immunocytochemistry; laboratory mouse; model design /development; motor neurons; nerve /myelin protein; nerve stem cell; nervous system regeneration; neurogenetics

Loss of motor neuron function causes reduction of lifespan: 1). Selective inhibition of motor neuron specification gene (HB or Nkx6.1) expression results in lethality at early developmental stages in the knockout mouse models; 2). Selective degeneration of matured motor neurons by overexpression of mutant SOD1 gene in the transgenic mouse (rat) models causes loss of motor function mimicking human amyotrophic lateral sclerosis (ALS). The long-term objective of this research application is to study the role of HB-9 expression in motor neuron regeneration and in extension of lifespan in the ALS-like transgenic mouse model. The hypothesis of the current research proposal is that the induction of HB-9 gene expression may induce motor neuron specification from neural precursor (stem) cells in vivo in a mouse model. The newly regenerated motor neurons may functionally replace the degenerated motor neurons and therefore may extend the lifespan of ALS-like transgenic mice. The following specific aims will be performed to test the hypothesis: Specific Aim 1: To generate transgenic mouse model for induction of HB-9 expression in neural precursor cells. Specifically, we will use the well-established Tet-on/TRE systems to define the induction conditions for expression of liB-9 in neural precursor cells of the bi-transgenic mice containing both pNestinrtTA and TRE-HB-9 transgenes. Specific Aim 2: To determine if the expression of HB-9 in neural precursor cells can promote motor neuron specification and regeneration. Specifically, we will use specific motor neuron markers to analyze HB-9-mediated motor neuron specification and differentiation (regeneration) in the bi-transgenic mouse spinal cord induced by Dox. The future research directions will focus on the tri-transgenic mouse model of motor neuron specification and regeneration on the improvement of motor function and the extension of lifespan in the ALS-like transgenic mouse system.

运动神经元功能丧失导致寿命缩短：1）。选择性抑制运动神经元特化基因（HB或Nkx6.1）表达导致敲除小鼠模型中早期发育阶段的致死性; 2）。在转基因小鼠（大鼠）模型中，通过过表达突变型SOD 1基因选择性地使成熟运动神经元变性，导致类似于人类肌萎缩侧索硬化症（ALS）的运动功能丧失。本研究应用的长期目标是研究HB-9表达在ALS样转基因小鼠模型中运动神经元再生和寿命延长中的作用。 目前研究建议的假设是，HB-9基因表达的诱导可能在小鼠模型中体内诱导神经前体（干）细胞的运动神经元特化。新生的运动神经元可能在功能上替代退化的运动神经元，从而可能延长ALS样转基因小鼠的寿命。将执行以下特定目标以检验假设： 具体目的1：建立用于诱导HB-9在神经细胞中表达的转基因小鼠模型 前体细胞具体而言，我们将使用完善的Tet-on/TRE系统来定义在含有pNestinrtTA和TRE-HB-9转基因的双转基因小鼠的神经前体细胞中表达liB-9的诱导条件。 具体目的2：确定HB-9在神经前体细胞中的表达是否可以促进运动神经元的特化和再生。具体来说，我们将使用特定的运动神经元标记物来分析HB-9介导的Dox诱导的双转基因小鼠脊髓中运动神经元的特化和分化（再生）。 运动神经元三转基因小鼠模型是今后的研究方向 在ALS样转基因小鼠系统中，本发明的目的在于提高ALS样转基因小鼠系统的运动功能和延长寿命。