Nemo-Like Kinase and the Pathogenesis of Spinal and Bulbar Muscular Atrophy

Nemo 样激酶与脊髓和延髓肌萎缩症的发病机制

基本信息

  • 批准号:
    8452770
  • 负责人:
  • 金额:
    $ 4.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-30 至 2014-09-29
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy's Disease) is an X-linked progressive neurodegenerative disease affecting the proximal spinal and bulbar motoneurons. Patients present in midlife with weakness of the limbs and facial fasciculation that often progresses to dysarthria and dysphagia, complications of which can lead to fatality. SBMA patients also commonly suffer from mild androgen insensitivity, presenting with symptoms including gynecomastia, testicular atrophy, and decreased fertility. SBMA is caused by an expansion of a polymorphic CAG trinucleotide repeat in the Androgen Receptor (AR) gene, classifying the disease as one of the nine polyglutamine (polyQ) disorders. PolyQ expansion renders the host protein toxic, resulting in the formation of mutant protein aggregates and cell death. The commonalities in the nature of the mutation and the presentation of the different polyQ disorders suggest the presence of a common pathogenic mechanism. Nonetheless, this mechanism has remained elusive and to date there are no cures or even effective therapeutics for many of these diseases. Studying the pathogenesis of one polyQ disorder, namely SBMA, should hopefully shed some light on the pathogenic mechanisms underlying all nine diseases. Furthermore, the only SBMA-specific therapeutics to have undergone clinical trials are aimed at reducing the androgen insensitivity would be beneficial in maintaining patient quality-of-life. This proposal therefore investigates the role of the serine/threonine protein kinase Nemo-Like Kinase (NLK) in the pathogenesis of SBMA with the hope that NLK will prove a viable drug target in the development of future therapeutics. Specifically, this application addresses the hypothesis that NLK promotes the SBMA disease condition via interacting with and modulating the polyQ-expanded mutant AR. To test this idea, the effect of NLK co- expression on an SBMA cellular model will be investigated using protein expression, immunofluorescence, and cytotoxicity techniques. Both established and novel Drosophila models of SBMA will be employed to determine if there is a genetic interaction between NLK and the mutant AR using both photoreceptor neurons and the motor neurons/neuromuscular junction as model tissues. Finally, the molecular mechanism underlying the interaction between NLK and AR will be investigated using transcription assays, molecular biology and genetic techniques in cellular and Drosophila models. Through this integrated approach of genetics, molecular biology, and in vivo disease models, this proposal seeks to define the role of NLK in promoting the SBMA disease condition, paving the way for future mammalian studies and ultimately allowing for the development of novel, non-anti-androgen therapeutics to treat this devastating disorder. PUBLIC HEALTH RELEVANCE: The polyglutamine diseases represent a class of devastating neurodegenerative disorders that afflict millions of people worldwide. Despite the fact that these diseases arise from a similar mutation and share various symptomatic features, the underlying pathogenic mechanisms remain poorly understood and effective therapeutics are therefore unavailable for many of these conditions1. This proposal explores the role of Nemo- Like Kinase (NLK) in the pathogenesis of one polyglutamine disease, Spinal and Bulbar Muscular Atrophy, with the aim that NLK may prove to be a target protein in the development of novel therapeutics.
描述(由申请人提供):脊柱和鳞茎肌肉萎缩(SBMA,肯尼迪病)是一种X连锁的进行性神经退行性疾病,影响近端脊柱和鳞茎运动神经元。在中年出现的患者肢体和面部束缚的弱点通常会发展为质心和吞咽困​​难,其并发症可能导致死亡。 SBMA患者也通常患有轻度的雄激素不敏感性,表现出包括妇科,睾丸萎缩和生育能力的症状。 SBMA是由雄激素受体(AR)基因中多态CAG三核苷酸重复膨胀引起的,将疾病归类为九种多谷氨酰胺(PolyQ)疾病之一。 Polyq膨胀会使宿主蛋白有毒,从而形成突变蛋白聚集体和细胞死亡。突变性质和不同PolyQ疾病的表现的共同点表明存在一种常见的致病机制。尽管如此,这种机制仍然难以捉摸,迄今为止,对于许多这些疾病,还没有治疗疗法,甚至还没有有效的治疗剂。研究一种PolyQ疾病的发病机理,即SBMA,应该有望阐明所有九种疾病的致病机制。此外,进行临床试验的唯一SBMA特异性治疗剂旨在降低雄激素不敏感性将有助于维持患者寿命。因此,该建议调查了 SBMA发病机理中的丝氨酸/苏氨酸蛋白激酶类黑素样激酶(NLK)希望NLK在发展未来的治疗剂的发展中证明NLK将是一个可行的药物靶标。具体而言,该应用解决了以下假设:NLK通过与PolyQ扩展的突变体AR相互作用并调节SBMA疾病条件。为了测试这一想法,将使用蛋白质表达,免疫荧光和细胞毒性技术研究NLK共同表达对SBMA细胞模型的影响。将使用SBMA的已建立和新型果蝇模型来确定使用光感受器神经元和运动神经元/神经肌肉连接作为模型组织的NLK和突变体之间是否存在遗传相互作用。最后,将使用转录测定,分子生物学和遗传技术研究细胞和果蝇模型中的NLK与AR之间相互作用之间的分子机制。通过这种遗传学,分子生物学和体内疾病模型的综合方法,该提案旨在定义NLK在促进SBMA疾病疾病中的作用,为未来的哺乳动物研究铺平了道路,并最终允许开发新型的,非抗抗血物的疗法来治疗这种破坏性疾病。 公共卫生相关性:聚谷氨酰胺疾病代表了一类毁灭性的神经退行性疾病,这些疾病困扰着全球数百万的人。尽管这些疾病是由类似的突变引起的,并且具有各种症状特征,但基本的致病机制仍然很了解,因此对于许多这些疾病中的许多疾病都无法获得有效的治疗方法1。该提案探讨了类似线酶(NLK)在一种多谷氨酰胺疾病,脊柱和鳞茎肌肉萎缩的发病机理中的作用,其目的是NLK可能被证明是新型治疗剂发展中的靶蛋白。

项目成果

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数据更新时间:2024-06-01

Tiffany Werlyne To...的其他基金

Nemo-Like Kinase and the Pathogenesis of Spinal and Bulbar Muscular Atrophy
Nemo 样激酶与脊髓和延髓肌萎缩症的发病机制
  • 批准号:
    8549780
    8549780
  • 财政年份:
    2012
  • 资助金额:
    $ 4.22万
    $ 4.22万
  • 项目类别:

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