Targeting axonal transport regulation by neurotrophic factors to treat peripheral nerve degeneration

通过神经营养因子调节轴突运输来治疗周围神经变性

• 批准号: MR/Y010949/1
• 负责人: James Sleigh
• 金额: $ 340.05万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY010949%2F1
• 关键词: Targeting; axonal; transport; regulation; neurotrophic

Charcot-Marie-Tooth disease (CMT) is an inherited nervous system disease that affects 1 in about 2,500 people, which makes it one of the most common diseases to affect both nerves and muscles. The symptoms of CMT usually begin during teenage years, but the disease does not affect survival, therefore it causes life-long disability, for which the estimated societal cost is approximately £0.5 billion per year in the UK alone. People with CMT have mobility issues and difficulties with sensation, because two different types of nerve cell, known as motor neurons and sensory neurons, malfunction and progressively deteriorate. It is unknown why these peripheral nerves are affected, which has made it difficult to develop treatments for CMT.Mutations in more than 100 different genes cause CMT, and the collection of genes linked to the most CMT subtypes all produce enzymes known as aminoacyl tRNA-synthetases (ARSs). The ARS enzymes are essential to all cells for making protein. To better understand how CMT is caused, we study two ARS genes - GARS1, which produces GlyRS protein and is linked to CMT type 2D (CMT2D) and YARS1, which produces TyrRS protein and is linked to a subtype known as DI-CMTC. Using cell and mouse models, we study CMT2D and DI-CMTC to understand why motor and sensory neurons deteriorate, because this will enable us to design better treatments to combat the disease.CMT-causing mutations in GARS1 and YARS1 affect the structure of the proteins they produce. My laboratory discovered that this causes mutant GlyRS and mutant TyrRS to mis-interact with a series of important proteins called Trk receptors, which are found on the surface of nerve cells and normally bind to survival molecules called neurotrophins.Recently, we have shown that the aberrant association between mutant ARS proteins and Trk receptors impairs a critical and continually active process in nerve cells known as axonal transport. Nerve cells have a long, thin pipe-like structure called an axon, which helps to deliver electrical signals and cellular components over large distances. For nerves to function correctly and survive, they require many substances to be delivered up and down axons by the process of axonal transport. In particular, motor and sensory neurons rely on this process to deliver neurotrophins from muscles towards the brain. We therefore boosted the levels of one of these key neurotrophins, BDNF, in muscles of CMT mice and showed that it can treat the disruption in axonal transport and improve other features of the disease. We now propose to examine in detail the role that neurotrophins and other similar neurotrophic factors (NTFs) play in regulating the process of axonal transport in motor and sensory nerves. Doing so, will not only allow us to better understand why these peripheral nerves deteriorate in CMT, but it will enable us to achieve our main goal, which is to develop a multi-pronged approach to treat the symptoms of CMT and improve patient quality of life.We will accomplish this through four main objectives:1) We will assess the structures of ARS and Trk receptor proteins, identifying exactly how they mis-interact, so that we can design treatments blocking specifically these aberrant associations.2) To identify key proteins other than NTFs that can be targeted to treat defects in axonal transport, we will generate and study new models of CMT2D and DI-CMTC using human motor neurons.3) By testing a collection of NTFs, we will identify whether molecules other than BDNF can be supplied to muscle to alleviate the axonal transport impairment in both human neurons and mice.4) We will adapt our treatment strategy to enable the continual and long-term delivery of BDNF, and other NTFs identified in Aim 3, to all muscles using harmless viruses and then test the effectiveness of these therapies in mouse models of several different subtypes of CMT.

Charcot-Marie-Tooth病（CMT）是一种遗传性神经系统疾病，影响了大约2500人中的1人，这使其成为影响神经和肌肉的最常见疾病之一。 CMT的症状通常在青少年时期开始，但是这种疾病不会影响生存，因此会导致终身残疾，仅英国仅在英国就每年的社会成本约为5亿英镑。患有CMT的人有活动性问题和感觉困难，因为两种不同类型的神经细胞，称为运动神经元和感觉神经元，故障和逐渐侦探。尚不清楚为什么这些周围神经受到影响，这使得很难开发CMT的治疗方法。超过100个不同基因的杂音会导致CMT以及与CMT最多的CMT亚型相关的基因的收集，这些酶都是生产的酶，称为氨基氨基含量TRNA-TRNA trNA-合作酶（ARSS）。 ARS酶对于所有细胞生产蛋白质都是必不可少的。为了更好地了解CMT是如何引起的，我们研究了两个ARS基因-GARS1，该基因产生Glyrs蛋白，并与CMT型2D（CMT2D）和YARS1相关，该基因产生了Tyrrs蛋白，并与称为Di -CMTC的亚型链接。使用细胞和小鼠模型，我们研究了CMT2D和DI-CMTC，以了解为什么运动和感觉神经元侦探，因为这将使我们能够设计更好的治疗方法来对抗疾病。GARS1和YARS1中的CMT引起的突变会影响其产生的蛋白质的结构。我的实验室发现，这会导致突变的聚糖和突变体与一系列称为TRK受体的重要蛋白质相互交流，这些蛋白质在神经细胞的表面上发现，通常与称为神经营养蛋白的存活分子结合。神经细胞具有长长的管状结构，称为轴突，这有助于在大距离内传递电信号和细胞成分。为了使神经正常运行并生存，它们需要通过轴突运输过程将许多物质在轴突上和向下传递。特别是，运动和感觉神经元依赖于这个过程来将神经营养蛋白从肌肉向大脑传递。因此，我们在CMT小鼠的肌肉中提高了这些关键神经营养蛋白BDNF的水平，并表明它可以治疗轴突运输的破坏并改善疾病的其他特征。现在，我们建议详细研究神经营养蛋白和其他类似的神经营养因子（NTF）在控制运动和感觉神经中轴突运输过程中发挥的作用。 Doing so, will not only allow us to better understand why these peripheral nerves detect in CMT, but it will enable us to achieve our main goal, which is to develop a multi-pronged approach to treat the symptoms of CMT and improve patient quality of life.We will accomplish this through four main objectives:1) We will assess the structures of ARS and Trk receptor proteins, identifying exactly how they mis-interact, so that we can design treatments blocking specifically these 2）要识别可用于治疗轴突运输中缺陷以外的其他关键蛋白质，我们将生成和研究使用人类运动神经元的CMT2D和DI-CMTC的新模型。3）3）通过测试NTF的收集，我们将确定其他分子以除其他分子以在bdnf中以供应的其他分子，以使其在型号中均以型号的含量为themant subair in humainf subson，以使其在型号中均在themirite subson中，以使其均在themirent thauls to subson to suff。 4）我们将适应我们的治疗策略，以使BDNF和AIM 3中的其他NTF的连续和长期递送使用使用无害病毒的所有肌肉，然后在几种不同亚型CMT亚型的小鼠模型中测试这些疗法的有效性。