Modeling Mutant Profilin 1 Toxicity and ALS in vivo

突变型 Profilin 1 毒性和 ALS 体内建模

基本信息

批准号：
8490556
负责人：
ZUOSHANG XU
金额：
$ 20.8万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8490556
关键词：
ADP-G-actin ATP-G-actin Actin-Binding Protein Actins Amyotrophic Lateral Sclerosis Animal Model Axon Binding Biological Models Brain C9ORF72 Cell model Cells Cessation of life Communities Complex Cultured Cells Data Disease Dissociation Endoplasmic Reticulum Familial Amyotrophic Lateral Sclerosis Family Future Gene Mutation Genes Genetic Growth Cones Injection of therapeutic agent Investigation Lead Manuscripts Microfilaments Mitochondria Modeling Morphology Motor Neuron Disease Motor Neurons Mus Mutation Nerve Degeneration Nervous system structure Neurites Neurodegenerative Disorders Neurons Nucleotides Oxidative Stress Paralysed Pathogenesis Pathway interactions Phenotype Population Positioning Attribute Prions Proteins RNA Processing Regulation Research Spinal Cord Testing Therapeutic Toxic effect Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Work angiogenin base computerized data processing dynactin exome sequencing gain of function genetic linkage analysis in vivo in vivo Model killings monomer motor neuron degeneration mouse model mutant novel overexpression polymerization profilin profilin 1 promoter protein TDP-43 public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), is a fatal neurodegenerative disease that kills motor neurons, leading to paralysis and death. The mechanism of motor neuron degeneration is not understood and the disease is currently incurable. Ten percent of ALS cases are familial and ninety percent are sporadic. Numerous genetic mutations have been identified to cause familial ALS, which include mutations in SOD1, ALS2, VAPB, senataxin, dynactin, angiogenin, TDP-43, FUS, UBQLN2 and c9orf72 genes. By investigating the mechanism whereby these mutants cause neurodegeneration in cellular and animal models, advances have been made in our understanding of the disease mechanism. Recently, by years of genetic studies we have discovered novel mutations in the profilin1 gene that cause ALS. Profilin is an actin-binding protein involved in regulation of actin dynamics and other important cellular signaling processes. Our preliminary experiments in cultured cells suggest that the PFN1 mutants can form intracellular aggregates, dominantly disrupt actin polymerization and growth cone morphology, leading to an inhibition of axon outgrowth. Based on these observations, we hypothesize that mutant profilin 1 cause neurodegeneration by a gain-of-function type of mechanism. To test this hypothesis, we propose to construct and analyze transgenic mice that overexpress mutant and wild type profilin 1. The results will provide evidence either for or against this hypothesis. In addition, if overexpression of mutant profilin 1 causes motor neuron degeneration, this experiment will also generate a new mouse model for ALS, which can be used by the ALS research community to explore the mechanism of motor neuron degeneration and test therapeutic strategies.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS，也称为卢伽雷氏病）是一种致命的神经退行性疾病，会杀死运动神经元，导致瘫痪和死亡。运动神经元变性的机制尚不清楚，目前该疾病无法治愈。百分之十的 ALS 病例是家族性的，百分之九十是散发性的。已确定多种基因突变可导致家族性 ALS，其中包括 SOD1、ALS2、VAPB、senataxin、dynactin、血管生成素、TDP-43、FUS、UBQLN2 和 c9orf72 基因的突变。通过研究这些突变体在细胞和动物模型中引起神经变性的机制，我们对疾病机制的理解取得了进展。最近，通过多年的遗传学研究，我们发现了导致 ALS 的 profilin1 基因的新突变。 Profilin 是一种肌动蛋白结合蛋白，参与肌动蛋白动力学和其他重要细胞信号传导过程的调节。我们在培养细胞中的初步实验表明，PFN1 突变体可以形成细胞内聚集体，显着破坏肌动蛋白聚合和生长锥形态，从而抑制轴突生长。基于这些观察，我们假设突变型 profilin 1 通过功能获得型机制引起神经变性。为了检验这一假设，我们建议构建并分析过度表达突变型和野生型 profilin 1 的转基因小鼠。结果将为支持或反对该假设提供证据。此外，如果突变型profilin 1的过度表达导致运动神经元变性，该实验还将生成一个新的ALS小鼠模型，可供ALS研究界探索运动神经元变性机制和测试治疗策略。