Modeling Mutant Profilin 1 Toxicity and ALS in vivo

突变型 Profilin 1 毒性和 ALS 体内建模

• 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
• 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

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）：肌萎缩性侧索硬化症（ALS，也称为Lou Gehrig's病）是一种致命的神经退行性疾病，可杀死运动神经元，导致瘫痪和死亡。运动神经元退化的机制尚不清楚，目前无法治愈。10%的ALS病例是家族性的，90%是散发性的。许多基因突变已被发现可导致家族性ALS，包括SOD1、ALS2、VAPB、senataxin、dynactin、angiogenin、TDP-43、FUS、UBQLN2和c9orf72基因突变。通过在细胞和动物模型中研究这些突变体导致神经变性的机制，我们对疾病机制的理解取得了进展。最近，经过多年的基因研究，我们发现了导致ALS的profin1基因的新突变。Profilin是一种肌动蛋白结合蛋白，参与调节肌动蛋白动力学和其他重要的细胞信号过程。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，主要破坏肌动蛋白聚合和生长锥形态，导致轴突生长受到抑制。基于这些观察，我们假设突变型profilin 1通过功能获得型机制导致神经退行性变。为了验证这一假设，我们提出构建并分析过表达突变型和野生型profilin1的转基因小鼠。研究结果将为支持或反对这一假设提供证据。此外，如果突变体profilin 1过表达导致运动神经元退行性变，本实验也将产生一种新的ALS小鼠模型，可用于ALS研究界探索运动神经元退行性变的机制和测试治疗策略。