Blocking chemotherapy-induced peripheral neuropathy by preserving axons

通过保留轴突阻止化疗引起的周围神经病变

基本信息

  • 批准号:
    MR/L003813/1
  • 负责人:
  • 金额:
    $ 75.84万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2013
  • 资助国家:
    英国
  • 起止时间:
    2013 至 无数据
  • 项目状态:
    已结题

项目摘要

Axons are long 'wires' that conduct electrical signals from one nerve cell (neuron) to another, or convey signals from sense organs or to muscles. Their extreme length (up to one meter) makes them vulnerable to many stresses, including inherited disorders, toxins, inflammation, viruses and physical injury. This results in disorders such as multiple sclerosis, diabetic neuropathy, motor neuron disease and glaucoma. Significant progress has been made in mice in understanding how axon degeneration can be prevented, or at least delayed, in response to many of these stresses and our group has played a prominent role in this work. However, until now it has not been clear how this could be translated for application in patients. One of the problems is that many of the stresses axons face are chronic and/or unpredictable. Long-term protection of axons, or protection at an unforeseen time, will always be more challenging that protecting them for a few days or weeks at a known time. One important disorder that fits this latter pattern is chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a dose-limiting side effect of many cancer drugs, causing intense pain. Most recipients of these cancer treatments suffer from it and around half of survivors continue to suffer afterwards, many for the rest of their lives. Recurrent stabbing, burning or tingling sensations, or numbness, particularly in hands and feet, regularly disrupt sleep and greatly reduce quality of life. Importantly, despite the long-term nature of the problem it stems from a very short and predictable treatment regime that causes axon degeneration. CIPN is an excellent candidate for preventative therapy. This project has three parts. First, we will build on encouraging data from mouse and cell culture studies indicating that a protein we have studied for many years protects axons in CIPN models. We will extend the previous studies by testing whether it preserves axons from damage by a wider range of chemotherapy drugs, whether it protects them indefinitely and whether it reduces the pain in addition to blocking axon degeneration. Second, we recently identified a drug that preserves axons by mimicking an effect of the protective gene, so we will test whether this drug preserves axons and prevents symptoms in CIPN animal models. Importantly, this drug is already in use in man (in clinical trials for cancer in fact) so if successful here, tests to determine whether it preserves axons in man could proceed quickly. Third, we aim to find out more about the mechanism that underlies the axon degeneration leading to CIPN. In particular, we focus on the transport of essential proteins and organelles along nerves, termed axonal transport, a process known to be disrupted by some cancer drugs. We will ask whether this is common to several drugs that induce CIPN, in what way is the transport disrupted, and what are the immediate consequences that lead to axon degeneration, an area in which our expertise in this field should ensure good progress. This will help us to develop further strategies to preserve axons in CIPN.Success in this project would be important for preventing the neurological complications that can result from cancer therapy. However, it should also be important in indicating how we might tackle other major axonal disorders. Diabetic neuropathy, which shares many symptoms with CIPN and affects over 1 million people in the UK, would be one excellent example. Multiple sclerosis, in which axons also come under temporary stress during inflammatory relapses, would be another. Until now there are no preventative therapies for any axonal disorders. By focusing on a disorder with a relatively straightforward mechanism, good animal models, and a very realistic likelihood of developing a therapy, it should be possible to make significant progress that provides important leads also for other important axonal diseases.
轴突是长的“电线”,将电信号从一个神经细胞(神经元)传导到另一个,或将信号从感觉器官或肌肉传递。他们的极端长度(长达一米)使他们容易受到许多压力,包括遗传性疾病,毒素,炎症,病毒和身体伤害。这导致诸如多发性硬化症、糖尿病性神经病、运动神经元疾病和青光眼的疾病。在理解如何预防或至少延迟轴突变性以应对许多这些压力方面,小鼠已经取得了重大进展,我们的小组在这项工作中发挥了突出作用。然而,到目前为止,还不清楚如何将其转化为应用于患者。其中一个问题是,轴突面临的许多压力是慢性的和/或不可预测的。轴突的长期保护,或在不可预见的时间内保护,总是比在已知的时间内保护它们几天或几周更具挑战性。符合后一种模式的一种重要疾病是化疗诱导的周围神经病变(CIPN)。CIPN是许多癌症药物的剂量限制性副作用,引起剧烈疼痛。这些癌症治疗的大多数接受者都患有这种疾病,大约一半的幸存者在之后继续遭受痛苦,许多人在余生中。反复出现的刺痛、烧灼感或刺痛感,或麻木感,特别是手和脚,经常扰乱睡眠,大大降低生活质量。重要的是,尽管问题的长期性,它源于一个非常短期和可预测的治疗方案,导致轴突变性。CIPN是预防性治疗的优秀候选者。该项目有三个部分。首先,我们将建立在小鼠和细胞培养研究的令人鼓舞的数据基础上,这些数据表明我们研究多年的蛋白质可以保护CIPN模型中的轴突。我们将通过测试它是否能保护轴突免受更广泛的化疗药物的损伤,是否能无限期地保护它们,以及是否能在阻断轴突变性的同时减轻疼痛来扩展以前的研究。其次,我们最近发现了一种通过模仿保护基因的作用来保护轴突的药物,因此我们将在CIPN动物模型中测试这种药物是否能保护轴突并预防症状。重要的是,这种药物已经在人类中使用(实际上是在癌症的临床试验中),因此如果在这里成功,确定它是否保留人类轴突的测试可以迅速进行。第三,我们的目标是找出更多的机制,轴突变性导致CIPN。特别是,我们专注于运输必需的蛋白质和细胞器沿着神经,称为轴突运输,一个已知的过程是由一些癌症药物中断。我们将问这是否是常见的几种药物,诱导CIPN,以何种方式中断的运输,以及什么是直接后果,导致轴突变性,在这一领域,我们的专业知识在这一领域应该确保良好的进展。这将有助于我们开发进一步的策略来保护CIPN中的轴突。该项目的成功对于预防癌症治疗可能导致的神经系统并发症非常重要。然而,它也应该是重要的,表明我们如何可能解决其他主要轴突疾病。糖尿病性神经病变与CIPN有许多共同的症状,在英国影响着超过100万人,这将是一个很好的例子。多发性硬化症是另一种疾病,在炎症复发期间,轴突也会受到暂时的压力。到目前为止,还没有预防性治疗任何轴突疾病。通过关注具有相对简单机制、良好动物模型以及开发治疗方法的非常现实可能性的疾病,应该有可能取得重大进展,为其他重要轴突疾病提供重要线索。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Protection against oxaliplatin-induced mechanical and thermal hypersensitivity in Sarm1-/- mice.
防止 Sarm1-/- 小鼠奥沙利铂诱导的机械和热过敏。
  • DOI:
    10.17863/cam.63967
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Gould S
  • 通讯作者:
    Gould S
Sarm1 haploinsufficiency or low expression levels after antisense oligonucleotides delay programmed axon degeneration.
  • DOI:
    10.1016/j.celrep.2021.110108
  • 发表时间:
    2021-12-14
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
    Gould SA;Gilley J;Ling K;Jafar-Nejad P;Rigo F;Coleman M
  • 通讯作者:
    Coleman M
Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport.
  • DOI:
    10.1016/j.neurobiolaging.2018.03.033
  • 发表时间:
    2018-08
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    Adalbert R;Milde S;Durrant C;Ando K;Stygelbout V;Yilmaz Z;Gould S;Brion JP;Coleman MP
  • 通讯作者:
    Coleman MP
Protection against oxaliplatin-induced mechanical and thermal hypersensitivity in Sarm1-/- mice
  • DOI:
    10.1016/j.expneurol.2021.113607
  • 发表时间:
    2021-01-23
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Gould, Stacey Anne;White, Matthew;Adalbert, Robert
  • 通讯作者:
    Adalbert, Robert
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Michael Philip Coleman其他文献

Michael Philip Coleman的其他文献

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{{ truncateString('Michael Philip Coleman', 18)}}的其他基金

The regulation of axon degeneration by SARM1
SARM1对轴突变性的调控
  • 批准号:
    BB/S009582/1
  • 财政年份:
    2019
  • 资助金额:
    $ 75.84万
  • 项目类别:
    Research Grant
Variability in human axon survival
人类轴突存活的变异性
  • 批准号:
    MR/N004582/1
  • 财政年份:
    2016
  • 资助金额:
    $ 75.84万
  • 项目类别:
    Research Grant
Blocking chemotherapy-induced peripheral neuropathy by preserving axons
通过保留轴突阻止化疗引起的周围神经病变
  • 批准号:
    MR/L003813/2
  • 财政年份:
    2015
  • 资助金额:
    $ 75.84万
  • 项目类别:
    Research Grant
A survival factor for axons: roles in disease and downstream mechanism
轴突的生存因素:在疾病和下游机制中的作用
  • 批准号:
    G1000702/1
  • 财政年份:
    2010
  • 资助金额:
    $ 75.84万
  • 项目类别:
    Research Grant
Spatio-temporal imaging of calcium in degenerating nerves
退化神经中钙的时空成像
  • 批准号:
    BB/D005159/1
  • 财政年份:
    2006
  • 资助金额:
    $ 75.84万
  • 项目类别:
    Research Grant

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A novel medical device for reducing chemotherapy-induced peripheral neuropathy in the hands
一种减少化疗引起的手部周围神经病变的新型医疗设备
  • 批准号:
    MR/Z503800/1
  • 财政年份:
    2024
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    $ 75.84万
  • 项目类别:
    Research Grant
Protecting spermatogonial stem cells from chemotherapy-induced damage for fertility preservation in childhood cancer
保护精原干细胞免受化疗引起的损伤,以保存儿童癌症的生育能力
  • 批准号:
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The Role of Astrocyte Elevated Gene-1 (AEG-1), A Novel Multifunctional Protein, In Chemotherapy-Induced Peripheral Neuropathy
星形胶质细胞升高基因 1 (AEG-1)(一种新型多功能蛋白)在化疗引起的周围神经病变中的作用
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