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Development of a New ALS Mouse Model that Targets Profilin1 and Actin Filaments

开发针对 Profilin1 和肌动蛋白丝的新型 ALS 小鼠模型

基本信息

批准号：
8969277
负责人：
Mahmoud Kiaei
金额：
$ 22.35万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969277
关键词：
Actins Address Amyotrophic Lateral Sclerosis Animal Disease Models Animal Model Astrocytes Axon Back Binding Body Weight decreased Brain Cell Survival Cell physiology Cells Cellular Structures Cessation of life Coculture Techniques Cytoskeleton Defect Dendrites Denervation Development Disease Disease Progression Engineering Equilibrium Exhibits Familial Amyotrophic Lateral Sclerosis Family Gait Genes Goals Growth Cones Hindlimb Human Individual Investigation Knowledge Length Microfilaments Microglia Mitochondria Modeling Molecular Motor Motor Neuron Disease Motor Neurons Mus Muscle Weakness Muscular Atrophy Mutant Strains Mice Mutation Nerve Degeneration Neurites Neuroglia Neuromuscular Junction Neurons Oxidative Stress Paralysed Pathology Patients Performance Pharmaceutical Preparations Phenotype Proteins Skeletal Muscle Spinal Cord Structure Tail Testing Therapeutic Therapeutic Intervention Transgenes Transgenic Mice Tremor Ursidae Family Valine Vesicle axon growth axonal degeneration base in vivo insight motor disorder motor neuron degeneration motor neuron function mouse model mutant mutant mouse model neurodegenerative phenotype neuroinflammation neuromuscular neuron loss new therapeutic target novel overexpression polymerization premature protein aggregation public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a devastating, lethal, motor neuron disease and, despite the fact that it has been identified for 140 years, there is no therapeutic intervention. The mechanisms causing the neurodegeneration are not known and animal models of the disease are limited. The need for additional animal models is tremendous and could further define mechanisms of disease and facilitate development of novel therapies for ALS. The recent breakthrough identifying profilin1 (PFN1) mutations in human familial ALS (fALS), presents us with the opportunity to develop a novel ALS model. Mutations in PFN1 disrupt the cytoskeleton by inhibiting polymerization of actin filaments. The consequences of this include disruption of key structures in neurons including the cytoskeleton, formation of axonal growth cones, inhibition of axon and dendrite outgrowth, and activities dependent on the actin cytoskeleton such as vesicle and mitochondria transport. To address the need for a mouse model of mutant PFN1 ALS that is expected to disrupt the cytoskeleton, we have produced transgenic mice overexpressing one of the mutations identified in familial ALS, a glycine118>valine substitution in the human PFN1 gene (hPFN1G118V). This model will provide an important opportunity to discover new, yet unknown cellular and molecular mechanisms that underlie neurodegeneration in ALS. Discoveries in this new mutant PFN1 ALS model will offer fundamental insights into pathogenic mechanisms and therapeutic intervention in ALS. We will use this model to test the hypothesis that expression of hPFN1G118V mutant protein in mice will cause cardinal phenotypes and pathologies that resemble those in ALS patients. Our hypothesis is based on preliminary characterization of hPFN1G118V transgene- expressing progeny. These mutant mice present degeneration and loss of motor neurons in the spinal cord, hindlimb tremor, clasping, muscle weakness and atrophy, reduced stride length, reduced general mobility, lower gait, hunched back, droopy tail, reduced motor performance, weight loss, and premature death. In this study, we propose to further characterize the ALS phenotype and neurodegenerative pathology in the hPFN1G118V model and investigate the cellular and molecular mechanisms of neurodegeneration caused by hPFN1G118V. Aim 1: Demonstrate that the functional phenotype and pathology of mutant hPFN1G118V transgenic mice resemble that of ALS patients. Aim 2: Define the mechanisms of mutant hPFN1G118V activity that underlie degeneration of motor neurons. This study will provide proof-of-principle that mouse models of mutant hPFN1 identified in ALS patients exhibit the phenotypes and pathologies of ALS. This will have significant impact because these models may unveil new mechanisms of ALS neurodegeneration applicable beyond the subset of familial ALS patients, providing new targets for therapeutic intervention. Further, these mice will provide a new model for therapeutic testing to stop progression of ALS-like neurodegeneration that may be translatable for human use.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种毁灭性的、致命的运动神经元疾病，尽管它已经被确定了140年，不是治疗性干预。引起神经变性的机制尚不清楚，并且该疾病的动物模型有限。对其他动物模型的需求是巨大的，可以进一步确定疾病的机制，并促进ALS新疗法的开发。最近在人类家族性ALS（fALS）中识别profilin1（PFN1）突变的突破，为我们提供了开发新型ALS模型的机会。PFN1的突变通过抑制肌动蛋白丝的聚合来破坏细胞骨架。其后果包括破坏神经元中的关键结构，包括细胞骨架，轴突生长锥的形成，轴突和树突生长的抑制，以及依赖于肌动蛋白细胞骨架的活动，如囊泡和线粒体运输。为了解决对预期破坏细胞骨架的突变型PFN1 ALS的小鼠模型的需求，我们已经产生了过表达在家族性ALS中鉴定的突变之一的转基因小鼠，所述突变是人PFN1基因中的甘氨酸118>缬氨酸取代（hPFN1G118V）。该模型将为发现ALS神经变性的新的、未知的细胞和分子机制提供重要机会。在这种新的突变PFN1 ALS模型中的发现将为ALS的致病机制和治疗干预提供基本见解。我们将使用该模型来检验hPFN1G118V突变蛋白在小鼠中的表达将导致类似于ALS患者的主要表型和病理的假设。我们的假设是基于hPFN1G118V转基因表达后代的初步表征。这些突变小鼠表现出脊髓中运动神经元的变性和丧失、后肢震颤、紧握、肌肉无力和萎缩、步幅缩短、一般活动性降低、步态降低、驼背、尾巴下垂、运动表现降低、体重减轻和过早死亡。在这项研究中，我们建议进一步表征ALS表型和hPFN1G118V模型中的神经退行性病变，并研究由hPFN1G118V引起的神经退行性病变的细胞和分子机制。目的1：证明突变型hPFN1G118V转基因小鼠的功能表型和病理学与ALS患者相似。目的2：明确突变型hPFN1G118V活性的机制，该机制是运动神经元变性的基础。这项研究将提供原理证明，在ALS患者中鉴定的突变hPFN1的小鼠模型表现出ALS的表型和病理学。这将产生重大影响，因为这些模型可能揭示适用于家族性ALS患者子集以外的ALS神经变性的新机制，为治疗干预提供新的靶点。此外，这些小鼠将为治疗测试提供新的模型，以阻止ALS样神经变性的进展，这可能可用于人类。