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英国一个研究肯尼迪病小组现在和即将进行的研究工作介绍

病友黑-阿米其检索到一篇英国的一个研究小组现在和即将进行的研究工作的介绍.现翻译如下,供病友们参考.

                Spinal and Bulbar Muscular Atrophy (SBMA)
                     Led by Dr Bilal Malik

  Spinal Bulbar Muscular Atrophy (SBMA) or Kennedy's Disease is an inherited adult onset, slowly progressing neuromuscular disorder characterised by the degeneration of lower motor neurons within the spinal cord and brainstem. SBMA is an X-linked disease, therefore it can only be passed on through females carriers of the gene. SBMA results from an abnormal expansion of the CAG polyglutamine encoding repeat within the androgen receptor gene. SBMA is therefore one of a group of nine neurodegenerative disorders, that includes Huntington’s disease, all caused by expansion of the CAG repeat within specific genes.The loss of motor neurons in SBMA results in muscle atrophy and weakness, involuntary muscle twitching and mild sensory impairment as well as signs of endocrine abnormalities. Since the disease is ligand (androgen)-dependent, disease manifest primarily in males, and females are usually asymptomatic. Although, there is widespread expression of the androgen receptor protein, the mechanism of selective motor neuron loss within the brainstem and spinal cord is largely unknown.
   Our research in SBMA is focused in two main areas: 1) establishing the underlying mechanisms of selective death of motor neurons in SBMA using cellular and mouse models of SBMA, and 2) identifying possible targets for therapeutic intervention and testing the efficacy of new compounds for their ability to modifying disease progression in SBMA mice.

Current projects include:
a.) Investigating axonal transport in a novel mouse model of SBMA.
  We have previously shown that unlike other neurodegenerative diseases such as Alzheimer’s, Huntington’s disease and ALS, a defect in axonal transport does not play a significant role in the pathogenesis of the AR100 mouse model of SBMA (Malik et al. 2011). This has important implications for design of treatment strategies for SBMA, which would be better focused on alternative targets. We are now investigating if any perturbation in axonal transport is present in a novel model of SBMA, the AR121 BAC transgenic mouse, in which the development of pathology is accelerated compared to the AR100 mice.

b.) Characterisation of a novel mouse model of SBMA.
 Our work has primarily been based on the well-characterized AR100 mouse model of SBMA, which reproduces key features and natural history of the human disease more accurately and develop a late-onset, gender-specific, progressive muscular phenotype similar to the disease manifested in SBMA patients. We now are undertaking a thorough behavioural and physiological characterisation of a new model of SBMA, the AR121 mice, developed by one of our collaborators. This will allow us to establish the development and course of the disease in these mice and assist in the design of future pre-clinical testing of potential treatment strategies in SBMA.
 
c.) Therapeutic intervention and pre-clinical testing
  By using arimoclomol, a co-inducer of the heat shock response, in the AR100 mice after the onset of symptoms, we have shown that it significantly ameliorated the disease phenotype of mice by improving hindlimb muscle force and contractile characteristics, improving motor neuron survival and upregulating the expression of the neurotrophic factor VEGF (Malik et al. 2013). It may therefore be beneficial in treating the pathology and symptoms underlying SBMA. We are currently evaluating the effectiveness of arimoclomol by treating AR100 mice presymptomatically as opposed to after the onset of symptoms in the first trial. This will potentially allow for the early treatment of patients, who may be diagnosed by genetic testing, well before the onset of disease. We plan to undertake similar analysis to test the efficacy of other compounds in modifying the course of disease and development of pathology in mouse models of SBMA.

d.) Investigating cell death pathways in SBMA
 We have observed a disturbance in ER-associated calcium homeostasis in cultured embryonic motor neurons from SBMA mice, which was accompanied by increased levels of ER stress presymptomatically, suggesting that ER stress may play an early and possibly causal role in disease pathogenesis (Montague et al. 2014),. We are now investigating if ER stress occurs downstream of a decrease in expression of calreticulin, an ER Ca2+ homeostasis protein, as a result of Fas activation and nitric oxide production. It is though that this cell death pathway may be specific to motoneurons in the mutant SOD1 model of ALS and we are currently testing this hypothesis by examining this pathway in SBMA mice. In addition we are looking at further pathways which may play a role in SBMA pathogenesis, such as the function of mitochondria, protein clearance (autophagy and the proteasome system) and the role of muscle in disease development.

e.) Transcriptomic analysis of SBMA mice.
 In order to identify candidate genes and molecular pathways which may be involved in early motoneuron perturbation in SBMA, we have undertaken a transcriptomic analysis of cultured embryonic motoneurons of the AR100 mouse model of SBMA. We have identified several key pathways and genes which underlie the pathology in SBMA. Currently we are analysing mRNA and miRNA expression using laser capture microdissection derived motoneurons from SBMA mice at different stages of the disease. This approach will allow us to characterise the molecular basis and pathways of early motoneuron dysfunction and death and may establish novel therapeutic strategies for SBMA treatment.

译文:

    脊髓延髓肌萎缩症或称肯尼迪病是一种成人发作的遗传病,特征为因脊髓和脑干下运动神经元变性而引起的缓慢进展的神经肌肉障碍.肯尼迪病是X连锁疾病,因此只能通过女性发病基因携带者遗传.肯尼迪病起因于雄激素受体基因内编码的多聚谷氨酰胺CAG重复数的异常扩张.因此肯尼迪病是九种神经变性疾病中的一种.这九种病里也包括亨廷顿病以及其它特定基因内CAG重复数扩张引起的疾病.肯尼迪病的运动神经元的死亡导致了肌肉的萎缩与虚弱,不自觉的肌肉抽搐和感觉障碍,以及内分泌的异常征象.由于这是一种雄激素受体依赖性疾病,因此发病主要是男性,而女性则没有症状.虽然在人体内雄激素受体蛋白到处分布,但是它有选择地只造成脑干和脊髓的运动神经元死亡,这一机制至今没有搞清楚.

   我们对肯尼迪病的研究主要集中在两个主要方面.1)确定肯尼迪病人的运动神经元被选择性杀死的潜在机制.这主要利用肯尼迪病的细胞和小鼠模型进行研究.2)辨别对肯尼迪病进行治疗干预可能性的靶目标并检验一些新的化合物药物对患肯尼迪病小鼠治疗效果的有效性.

 目前的项目包括:

 a) 研究一种新类型的患肯尼迪病小鼠的轴突传输过程.
 我们以前的研究表明,肯尼迪病并不像其它神经变性疾病,如阿尔兹海默症,亨廷顿症以及渐冻人症那样,而是在AR100小鼠模型发病机制中,其轴突运输的缺陷并不起重要作用。这对我们在治疗策略的设计上有着重要的启示,使我们能够更好地集中于替代靶目标的研究.我们现在正在研究在一个新的小鼠模型中是否表现出轴突运输的任何扰动,这种新的,标号AR121 BAC 的转基因小鼠相对于原来的AR100小鼠其病理发展会加速进行.

 b.)肯尼迪病新的小鼠模型的特征
 我们前期已经完成的工作是基于肯尼迪病AR100小鼠模型进行的.这一模型能够再现关键的特征,较准确地反映人类疾病的自然史和后期的发病进程,性别特征,以及类似于肯尼迪病患者的渐进的肌肉表现.我们现在正在利用一个由我们的合作者开发的新的肯尼迪病模型,即AR121小鼠,进行较为彻底的行为特性和生理特性的研究.这将使我们能够确定在这类小鼠中的疾病发展和进程,帮助我们对未来进行的前期肯尼迪病临床试验作出治疗策略的设计.

c.)治疗干预和临床前检查
 在AR100小鼠病情发作以后,通过使用arimoclomol,一种热休克蛋白响应的辅助诱导剂,我们发现它能够通过改进后肢肌肉的力量及收缩能力,增进运动神经元的存活,上调神经营养因子VEGF的表达,从而显著改善小鼠疾病的表现.所以它可能是改善肯尼迪病病理及症状的有益的药物(译者:指的是arimoclomol这种药物).现在我们正在通过处理AR100小鼠症状发生之前和症状发生以后的情况,对 arimoclomol的有效性进行首次的评价.这可能允许我们对通过基因检测确诊的,但是还没有发病的潜在病人进行较早的治疗.我们还计划进行类似的分析,以测试其他化合物药物在改善肯尼迪病小鼠模型的疾病病理发展过程的功效.

d.)研究肯尼迪病细胞死亡的途径
 我们现在正在通过检测肯尼迪病小鼠细胞死亡路径来验证提出的一种细胞死亡路径的假设.此外,我们正在寻找可能的进一步的新路径.这种新的路径很可能在肯尼迪病的发病机制中起到很重要的作用,如在线粒体功能、蛋白质清除(自噬与蛋白酶体系统)以及肌肉在疾病发展中的作用.

 e.)SBMA小鼠的转录组分析
 为了确定候选基因和分子的途径,它们可能涉及肯尼迪病早期运动神经元的扰动,我们已经进行了AR100肯尼迪病小鼠培养的胚胎神经元转录组分析.我们已经确定了几个关键的路径和涉及肯尼迪病的基因.最近我们对发病在不同阶段的肯尼迪病小鼠,利用激光捕获显微切割衍生运动神经元技术分析了mRNA和miRNA的扩展情况.这一方法可以使我们了解早期运动神经元功能发生障碍和死亡的分子过程和发生的路径,也可能使我们在治疗肯尼迪病上建立新的治疗策略。



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