Novel ALS models: FUS conditional knockout in motor neurons and oligodendrocytes

新型 ALS 模型：运动神经元和少突胶质细胞中的 FUS 条件敲除

基本信息

批准号：
9210545
负责人：
FRANCA CAMBI
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9210545
关键词：
Adult Affect Amyotrophic Lateral Sclerosis Area Award Breathing Cells Clinical Trials Cytoplasm Cytoplasmic Granules DNA Data Defect Development Disease Drosophila genus Functional disorder Funding Future Genes Goals Health Benefit Human Inherited Intervention Knock-out Knockout Mice Knowledge Laboratories Locomotion Male Sterility Mediating Metabolism Modeling Molecular Molecular Target Motor Motor Neuron Disease Motor Neurons Mus Mutation Neonatal Nerve Degeneration Nervous system structure Neuroglia Neurons Nuclear Nuclear Export Nuclear Localization Signal Oligodendroglia Pathogenicity Pathologic Phenotype Pilot Projects Play Proteins RNA Reagent Research Research Personnel Role Signal Transduction Spinal Cord Stress Supporting Cell Testing Veterans Zebrafish age related base disease-causing mutation effective therapy falls gain of function gene discovery in vivo innovation loss of function motor neuron degeneration mouse model mutant neuron loss neurotoxicity novel novel therapeutic intervention novel therapeutics overexpression public health relevance sarcoma

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS) is an invariably fatal disorder caused by degeneration of the upper and lower motor neuron. Presently, there are no effective therapies. Many promising interventions have failed in clinical trials. New therapies are needed and their development will depend on advances in our knowledge of mechanisms of motor neuron degeneration and of the support provided by the surrounding glia. Fused in sarcoma (FUS) is one of the latest genes discovered to cause familial and sporadic ALS. It is one of a growing number of RNA/DNA processing genes associated with familial and sporadic ALS. This discovery has further highlighted the pivotal role that defects in RNA/DNA function and processing have in neurodegeneration. A major unanswered question is whether loss of FUS function contributes to neuronal degeneration. Ours and other investigators studies support the notion that loss of nuclear function(s) plays a role in motor neuron degeneration, however, the importance of loss of function mechanism in vivo remains to be determined. Another critical question is whether neurodegeneration caused by FUS defects is cell-autonomous. Our studies in Drosophila suggest a glia-based mechanism of neurotoxicity. The hypothesis to be tested in this project is that loss of FUS function is a critical mechanism to cause motor neuron degeneration and non cell-autonomous FUS neurotoxicity mediated by oligodendrocytes plays an important role in ALS. Constitutive FUS knockout in mice resulted in neonatal lethality and male sterility, hence these mice cannot be used to investigate the role of loss of FUS in vivo in the adult nervous system. To fill this gap in knowledge, we will make FUS conditional knockout mice in which FUS is depleted in either motor neurons or oligodendrocytes and characterize age-dependent motor neuron loss and associated phenotypes. We have made a FUSfl/fl mouse line and we are ready to cross it with neuronal and oligodendrocyte Cre expressing lines. We will perform motor, pathological and molecular studies to determine whether FUS deficient motor neurons undergo age-dependent degeneration and whether FUS deficient oligodendrocytes contribute to motor neuron loss. Future studies will investigate the molecular mechanisms of disease in these two models. The ultimate goal is to generate models in which molecular targets can be identified, characterized and used to test novel therapeutic interventions for ALS. Collectively, these studies will fill an important gap in knowledge and will generate valuable mouse models that will be used to investigate disease mechanisms and serve as in vivo platforms to test compounds aimed at slowing progression of motor neuron loss. These studies have a great potential to generate results and reagents that will advance the field of ALS research and will benefit the health of Veterans with motor neuron disorders.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是由上和下运动神经疗法导致的致命性。周围的神经胶质（FUS）是被发现引起家族性和零星的一个晚期基因之一。遗传者的研究概念在运动神经元变性中起作用，功能丧失的重要性仍有待确定在果蝇中，在该项目中测试了一种基于胶质的神经病的机制，是ofuss作为关键机械性机械性神经元退化，非细胞自主神经神经毒性由少突胶质细胞介导的，在ALS中起着卑鄙的作用。在成人神经系统中，男性在体内损失了这一知识的差距，我们将在任何一个运动神经元中耗尽FUS的资金敲除小鼠。 /fl小鼠线和我们准备与表达线的神经性细胞CRE交叉。 LS。最终目标是生成模型，其中分子目标可以研究填充知识的差距，并将成为有价值的穆斯群，这些鼠标将使toused toused tousede mosede mosede mosease Mosease Mosease Mosease Mosease和Erve作为体内平台，以测试旨在减慢运动神经元的范围的化合物损失。