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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性侧索硬化症（ALS）的主要特征，ALS是一种进行性神经退行性疾病，可导致瘫痪和死亡。尽管大多数运动神经元在ALS中死亡，但一些群体对退化有抵抗力。这一探索性提议旨在比较运动神经元中抵抗ALS的基因表达和易受ALS影响的基因表达。这些实验的长期目标是确定赋予某些运动神经元保护的基因，并最终诱导这些基因在通常屈服于ALS的运动神经元中的表达。为了实现这些目标，我们将在野生型和ALS转基因大鼠中比较球海海绵核和动眼肌核（抗ALS的运动神经元群体）与背外侧后核和三叉神经核（易患ALS的运动神经元群体）的基因表达。具体目的1：比较不同ALS易感性运动神经元群体中的基因表达。这些实验将使用基因微阵列分析经过激光捕获显微解剖和RNA扩增的运动神经元。特异性目的2：检测ALS易感性差异运动神经元中特异性基因的表达。这些实验将使用RT-PCR，原位杂交和免疫组织化学。特异性目的3：确定与ALS抗药运动神经元相关的分子是否在ALS转基因大鼠模型中受到差异影响。这些实验将在转基因SOD-1突变大鼠中使用Specific Aim 2技术。运动神经元的死亡是ALS的一个特征，ALS是一种致命的瘫痪性神经系统疾病。了解一些运动神经元群体如何抵抗变性，甚至在疾病晚期，可能为ALS中有变性风险的运动神经元的基因治疗靶点提供线索。