Development of mouse models of optineurin-linked ALS

optineurin 相关 ALS 小鼠模型的开发

• 批准号: 8428434
• 负责人: Han-Xiang Deng
• 金额: $ 23.18万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8428434
• 关键词: Accounting; Affect; Amyotrophic Lateral Sclerosis; Autophagocytosis; Biochemical; Brain; Cessation of life; Characteristics; Clinical Trials; Communities; Data; Deposition; Development; Disease; Etiology; Familial Amyotrophic Lateral Sclerosis; Family; Genetic; Human; Impairment; In Vitro; Indium; Individual; Investigation; Knockout Mice; Knowledge; Link; Methods; Molecular; Motor Neurons; Mus; Mutation; Neurodegenerative Disorders; Paralysed; Pathogenesis; Pathologic; Pathway interactions; Patients; Population; Property; Proteins; Recording of previous events; Research; Research Personnel; Respiratory Failure; Rest; Role; Screening procedure; Spinal; Spinal Cord; System; Testing; The Jackson Laboratory; Therapeutic; Therapeutic Effect; Transgenic Mice; Transgenic Organisms; Ubiquitin; base; drug testing; effective therapy; in vivo; interest; motor neuron degeneration; mouse model; multicatalytic endopeptidase complex; mutant; novel; overexpression; protein degradation; tool

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by degeneration of motor neurons in the brain and spinal cord, eventually leading to respiratory failure and death. ALS affects an estimated 350,000 individuals worldwide, with 50% dying within 3 years of onset. Most ALS cases are sporadic (SALS) of unknown etiology. About 5-10% of ALS cases have a family history (FALS). Mutations in optineurin (OPTN) have been shown to cause ALS in different populations through an unknown mechanism. We have recently shown that OPTN is a common component in the ALS-characteristic skein-like inclusions in the spinal motor neurons of all ALS cases, except for those with SOD1 mutations. Our data, together with those from previous studies of TDP43 and FUS provide important evidence supporting the hypothesis that: (I) most of ALS, including sporadic ALS and SOD1-negative FALS (accounting for approximately 97% of all ALS cases), may share some common elements in the disease pathogenesis, although there is great diversity in the cause~ and (II) the pathogenesis of SOD1-linked ALS (accounting for approximately 3% of all ALS cases) may be largely distinct from the rest of ALS. Currently, there is no effective treatment for ALS. A large number of clinical trials have been carried out, but have failed to show promising results. Some compounds showed therapeutic effect on the SOD1G93A ALS mouse model (the most widely use ALS mouse model for ALS research and drug testing), but not subsequently on ALS patients in clinical trials, possibly due to the difference of pathogenic pathways between SOD1-linked ALS and the rest forms of ALS, as suggested by OPTN, FUS and TDP43 pathological studies. Development of rational and effective therapies for this devastating disease is largely hindered by limited knowledg about its pathogenic mechanism. Pathogenesis of OPTN-linked ALS is largely unknown and its relation to other forms of ALS remains to be elucidated. Our preliminary in vitro data suggest that OPTN and UBQLN2 have a convergent role in autophagy and UPS, and impairment of autophagy and UPS by OPTN and UBQLN2 mutations may contribute to motor neuron degeneration in ALS. OPTN-linked ALS mouse models should be valuable tools for further investigation of the in vivo pathogenic mechanisms. In this application, we propose to develop three mouse models: OPTNWT transgenic, OPTNE478G transgenic and optn knockout (optn-/-) mouse models. We will deposit these mice to the Jackson Laboratories as soon as they are established. Successful completion of this project will be highly likely to provide valuable tools for the research community to study not only the OPTN-linked ALS, but also the convergence of pathogenic mechanisms of sporadic ALS and familial ALS caused by different genetic defects. Moreover, these mouse models may also be used for screening and testing potential therapeutic approaches. PUBLIC HEALTH RELEVANCE: Mutations in optineurin (OPTN) have been shown to cause ALS, but the disease mechanism remains to be elucidated. In this application, we propose to develop and characterize novel OPTN-linked ALS mouse models and make these mouse models available to the research community. Successful completion of this project will provide valuable tools for the research community to study not only the OPTN-linked ALS, but also the convergence of pathogenic mechanisms of sporadic ALS and familial ALS caused by different genetic defects. Moreover, these mouse models may also be used for screening and testing potential therapeutic approaches.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是一种麻痹性疾病，通常是由大脑和脊髓中运动神经元变性引起的，最终导致呼吸衰竭和死亡。 ALS在全球范围内影响大约350,000个个人，在发病后3年内死亡50％。大多数ALS病例是未知病因的零星（SAL）。大约5-10％的ALS病例具有家族史（FALS）。 Optineurin（OPTN）中的突变已证明通过未知机制导致不同种群的ALS。我们最近表明，除了患有SOD1突变的患者外，OPTN是所有ALS病例的脊柱运动神经元中ALS类链球样夹杂物的常见成分。我们的数据，以及先前对TDP43和FUS研究的数据提供了重要的证据，支持以下假设：（i）大多数ALS，包括零星ALS和SOD1阴性fals（大约97％的ALS病例），可能会在疾病病原体中具有很大的不同元素，尽管AL中有很大的变化，但该病因是CADENS的各种元素。在所有ALS案例中）可能与其他ALS的其他部分不同。目前，ALS没有有效的治疗方法。 已经进行了大量临床试验，但未能显示出令人鼓舞的结果。一些化合物对SOD1G93A ALS小鼠模型（最广泛使用的ALS小鼠模型进行ALS研究和药物测试）显示出治疗作用，但随后在临床试验中对ALS患者没有，可能是由于该患者的 如OPTN，FUS和TDP43病理学研究所示，SOD1连接ALS与ALS的其余形式之间的致病途径差异。 有限的关于其致病机制的知识有限，为这种毁灭性疾病的有效疗法的发展开发。 OPTN连锁ALS的发病机理在很大程度上是未知的，其与其他形式的ALS的关系仍有待阐明。我们的初步体外数据表明，OPTN和UBQLN2在自噬和UPS中具有收敛作用，并且OPTN和UBQLN2突变​​对自噬和UPS的损害可能有助于ALS的运动神经元变性。 OPTN连接的ALS小鼠模型应该是进一步研究体内致病机制的有价值工具。在此应用程序中，我们建议开发三种鼠标模型：Optnwt转基因，Optne478g转基因和Optn敲除（OPTN - / - ）鼠标模型。我们将在建立后立即将这些老鼠存放到杰克逊实验室。 成功完成该项目将很可能提供有价值的工具 对于研究界，不仅要研究OPTN连接的ALS，还要研究零星ALS和由不同遗传缺陷引起的零星ALS和家族性ALS的致病机制的收敛。 此外，这些小鼠模型也可以用于筛选和测试潜在的治疗方法。 公共卫生相关性：已证明Optineurin（OPTN）突变会引起ALS，但疾病机制仍有待阐明。在此应用程序中，我们建议开发和表征新型的OPTN链接ALS鼠标模型，并使这些鼠标模型可用于研究社区。该项目的成功完成将为研究界提供宝贵的工具，不仅研究了OPTN连接的ALS，还可以研究零星ALS和由不同遗传缺陷引起的零星ALS和家族性ALS的致病机制的收敛。 此外，这些小鼠模型也可以用于筛选和测试潜在的治疗方法。