Gene Expression in Motor Neurons with Differential Susceptibility to ALS

对 ALS 易感性不同的运动神经元的基因表达

基本信息

批准号：
8269638
负责人：
Elizabeth Gould
金额：
$ 22.67万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269638
关键词：
Address Affect Amyotrophic Lateral Sclerosis Animals Calcium Calcium-Binding Proteins Cell Death Cell Nucleus Cell Survival Cessation of life Disease Disease Resistance Exhibits Gene Expression Gene Proteins Genes Goals Homologous Gene Immune Immunohistochemistry In Situ Hybridization Injection of therapeutic agent Label Lumbosacral Region Major Histocompatibility Complex Microarray Analysis Modeling Molecular Motor Motor Neurons Mus Muscle Mutant Strains Mice Neurodegenerative Disorders Neurons Neurotransmitter Receptor Oculomotor nucleus Paralysed Patients Polymerase Chain Reaction Population Predisposition RNA RNA amplification Rattus Reporting Resistance Reverse Transcription Risk Rodent Sampling Services Spinal Staging Superoxide Dismutase System Techniques Testing Tissue-Specific Gene Expression Tracer Transgenic Mice Transgenic Organisms Trigeminal Nuclei Vulnerable Populations base design end stage disease excitotoxicity foot gene therapy hippocalcin interest laser capture microdissection mRNA Expression motor neuron degeneration mutant nervous system disorder neurodevelopment penis receptor repaired research study sphincter ani muscle structure urinary

项目摘要

DESCRIPTION (provided by applicant): Motor neuron death is a major feature of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that leads to paralysis and death. Although most motor neurons die in ALS, some populations are resistant to degeneration. This exploratory proposal is designed to compare gene expression in motor neurons that are resistant to ALS with those that are vulnerable to ALS. The long term objectives of these experiments are to identify genes that confer protection to certain motor neurons and, ultimately, to induce expression of these genes in motor neurons that typically succumb to ALS. To accomplish these goals, we will compare gene expression in the bulbocavernosus and oculomotor nuclei, motor neuron populations that are resistant to ALS, with gene expression in the retrodorsolateral and trigeminal nuclei, motor neuron populations that are vulnerable to ALS, in both wildtype and ALS transgenic rats. The following aims will be investigated: Specific Aim 1: Compare gene expression in populations of motor neurons with differential susceptibility to ALS. These experiments will use gene microarray analysis of motor neurons after laser capture microdissection and RNA amplification. Specific Aim 2: Examine expression of specific genes identified in motor neurons with differential susceptibility to ALS. These experiments will use RT-PCR, in situ hybridization and immunohistochemistry. Specific Aim 3: Determine whether molecules associated with ALS- resistant motor neurons are differentially affected in a transgenic rat model of ALS. These experiments will use the techniques of Specific Aim 2 in transgenic SOD-1 mutant rats. Death of motor neurons is a hallmark of ALS, a paralyzing neurological disease that is fatal. Understanding how some motor neuron populations resist degeneration, even in late stage disease, may provide clues about targets for gene therapy in motor neurons at risk for degeneration in ALS.

描述（由申请人提供）：运动神经元死亡是肌萎缩侧索硬化症（ALS）的主要特征，ALS 是一种导致瘫痪和死亡的进行性神经退行性疾病。尽管大多数运动神经元在 ALS 中死亡，但有些群体能够抵抗退化。该探索性提案旨在比较对 ALS 具有抵抗力的运动神经元和易受 ALS 影响的运动神经元中的基因表达。这些实验的长期目标是鉴定为某些运动神经元提供保护的基因，并最终诱导这些基因在通常死于 ALS 的运动神经元中表达。为了实现这些目标，我们将比较野生型和 ALS 中球海绵体和动眼神经核（对 ALS 具有抵抗力的运动神经元群）中的基因表达与后背外侧核和三叉神经核（易受 ALS 影响的运动神经元群）中的基因表达。转基因大鼠。将研究以下目标：具体目标 1：比较对 ALS 易感性不同的运动神经元群体中的基因表达。这些实验将在激光捕获显微切割和 RNA 扩增后对运动神经元进行基因微阵列分析。具体目标 2：检查对 ALS 易感性不同的运动神经元中确定的特定基因的表达。这些实验将使用 RT-PCR、原位杂交和免疫组织化学。具体目标 3：确定与 ALS 抗性运动神经元相关的分子在 ALS 转基因大鼠模型中是否受到不同程度的影响。这些实验将在转基因 SOD-1 突变大鼠中使用 Specific Aim 2 技术。运动神经元死亡是 ALS 的一个标志，ALS 是一种致命的麻痹性神经系统疾病。了解一些运动神经元群如何抵抗变性，即使是在疾病晚期，也可能为有 ALS 变性风险的运动神经元的基因治疗靶点提供线索。