Investigating the molecular mechanisms of mutant C9orf72 human iPSC-derived astrocyte-mediated motor neuron deficits

研究突变型 C9orf72 人 iPSC 衍生的星形胶质细胞介导的运动神经元缺陷的分子机制

基本信息

批准号：
MR/T000708/1
负责人：
MARIA STAVROU
金额：
$ 27.51万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT000708%2F1
关键词：
Investigating molecular mechanisms mutant C9orf72

项目摘要

How bad is it doctor? How long do I have? Why aren't there any treatments doctor?Those were the questions I was asked by a 35-year old man on the day I conveyed the devastating diagnosis of Amyotrophic Lateral Sclerosis or ALS to him. The day when his life's path was irreversibly altered, the day when his roles as a partner, parent, professional, caregiver blurred into that of the patient. Within a year, this fit young man became wheelchair- and respirator-dependent, and six months after that he succumbed to the disease. ALS is a degenerative and deadly neurological disorder, with 80% of patients dying within 5 years of diagnosis. The shocking pace of the disease results in a frightening journey of physical decline for the patients, who lose the ability to move their arms and their legs, speak, swallow and eventually, breathe. It was 1874 when the French neurologist Jean-Martin Charcot gave this disease a name and pinpointed its cause in neurological problems of a mysterious nature. In the past few years, important discoveries about ALS have been made. Disappointingly, however, that knowledge has not yet turned into clinical breakthroughs to make a difference to our patients. To date no cure has been found. Why? Firstly, the brain is the most complex organ of the body and traditionally, drugs have been tested in animals rather than humans. As Alexander Pope said, 'the proper study of mankind is man'. Secondly, the brain cells that neighbour the nerve cells have long been neglected.The building blocks of the brain are the nerve cells called neurons, but they do not live in isolation. They're surrounded by cells called glia (from the Greek word meaning 'glue') that are important for the growth and survival of neurons. Amongst the three types of glial cells, the astrocytes - named for their star-like shape - are the largest and most numerous brain cells in humans compared to all animal species. If the human brain were the night sky, the astrocytes would be the twinkling stars infusing it with brightness and vitality. Astrocytes are now in the neuroscience limelight. They regulate nerve cells and their environment by providing essential nutrients, cleaning up waste and helping to repair the damaged brain and spinal cord. My research focuses on understanding the role of astrocytes in ALS. With the help of stem cell technology and scientific 'cookery', I will study 'human disease in a dish'. I will compare astrocytes from healthy individuals with those from people with ALS carrying a specific gene mutation. This gene mutation is the most common genetic cause of ALS. I will grow the healthy and ALS astrocytes with human motor neurons and I will examine their effects on the health and architecture of the neurons. If the healthy and ALS astrocytes affect motor neurons differently, I will test whether the effects are due to direct contact of motor neurons with the ALS astrocytes or the consequence of the release of toxic substances by astrocytes, or both. Using state-of-the-art techniques, I will try to identify the genes, proteins and pathways affected, in the hope of finding ways to slow, stop or even reverse the disease process. Through our research and the ongoing support from people with ALS, I do think that the day we might be able to repair the damaged brain will come sooner than we think.

医生的情况有多严重？我还有多长时间？为什么没有治疗医生？当我向一位 35 岁的男子传达肌萎缩侧索硬化症或 ALS 的毁灭性诊断结果那天，他问了我这些问题。那一天，他的人生道路发生了不可逆转的改变，那一天，他作为伴侣、父母、专业人士、护理人员的角色与病人的角色变得模糊起来。一年之内，这位健康的年轻人开始依赖轮椅和呼吸器，六个月后他死于这种疾病。 ALS 是一种致命的退行性神经系统疾病，80% 的患者在诊断后 5 年内死亡。这种疾病的惊人发展速度导致患者身体出现可怕的衰退，他们失去了移动手臂和腿、说话、吞咽以及最终呼吸的能力。 1874 年，法国神经学家让-马丁·夏科 (Jean-Martin Charcot) 为这种疾病命名，并指出了其在神秘神经系统问题中的病因。过去几年，关于 ALS 的重要发现不断涌现。然而，令人失望的是，这些知识尚未转化为临床突破，为我们的患者带来改变。迄今为止尚未找到治愈方法。为什么？首先，大脑是身体最复杂的器官，传统上，药物是在动物而不是人类身上进行测试的。正如亚历山大·波普所说，“对人类的正确研究是人”。其次，与神经细胞相邻的脑细胞长期以来一直被忽视。大脑的组成部分是称为神经元的神经细胞，但它们并不是孤立存在的。它们被称为神经胶质细胞（来自希腊语，意思是“胶水”）的细胞包围，这些细胞对神经元的生长和生存很重要。在三种类型的神经胶质细胞中，星形胶质细胞因其星状形状而得名，是人类与所有动物物种相比最大、数量最多的脑细胞。如果说人脑是夜空，那么星形胶质细胞就是闪烁的星星，为夜空注入光明和活力。星形胶质细胞现在成为神经科学的焦点。它们通过提供必需的营养、清理废物并帮助修复受损的大脑和脊髓来调节神经细胞及其环境。我的研究重点是了解星形胶质细胞在 ALS 中的作用。借助干细胞技术和科学“烹饪”，我将研究“菜肴中的人类疾病”。我将比较健康个体的星形胶质细胞与携带特定基因突变的 ALS 患者的星形胶质细胞。这种基因突变是 ALS 最常见的遗传原因。我将用人类运动神经元培养健康的 ALS 星形胶质细胞，并检查它们对神经元健康和结构的影响。如果健康星形胶质细胞和 ALS 星形胶质细胞对运动神经元的影响不同，我将测试这种影响是否是由于运动神经元与 ALS 星形胶质细胞直接接触所致，还是星形胶质细胞释放有毒物质的结果，或两者兼而有之。我将利用最先进的技术，尝试识别受影响的基因、蛋白质和通路，希望找到减缓、阻止甚至逆转疾病进程的方法。通过我们的研究和 ALS 患者的持续支持，我确实认为我们能够修复受损大脑的那一天会比我们想象的更早到来。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Experiences of remote consulting for patients and neurologists during the COVID-19 pandemic in Scotland.

DOI：
10.1136/bmjno-2021-000173
发表时间：
2021
期刊：
BMJ neurology open
影响因子：
2.7
作者：
Stavrou M;Lioutas E;Lioutas J;Davenport RJ
通讯作者：
Davenport RJ

Blood-CNS barrier dysfunction in amyotrophic lateral sclerosis: Proposed mechanisms and clinical implications.

DOI：
10.1177/0271678x231153281
发表时间：
2023-05
期刊：
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
影响因子：
6.3
作者：
Steinruecke, Moritz;Lonergan, Rebecca Murphy;Selvaraj, Bhuvaneish T.;Chandran, Siddharthan;Diaz-Castro, Blanca;Stavrou, Maria
通讯作者：
Stavrou, Maria

Neurological, Neuropsychiatric and Psychiatric Symptoms During COVID- 19 Infection and After Recovery: A Systematic Review of Observational Studies

COVID-19 感染期间和康复后的神经、神经精神和精神症状：观察性研究的系统回顾

DOI：
10.32474/ojnbd.2021.06.000228
发表时间：
2021
期刊：
Online Journal of Neurology and Brain Disorders
影响因子：
0
作者：
Stavrou M
通讯作者：
Stavrou M

Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective.

DOI：
10.1093/braincomms/fcab242
发表时间：
2021
期刊：
Brain communications
影响因子：
4.8
作者：
Wong C;Stavrou M;Elliott E;Gregory JM;Leigh N;Pinto AA;Williams TL;Chataway J;Swingler R;Parmar MKB;Stallard N;Weir CJ;Parker RA;Chaouch A;Hamdalla H;Ealing J;Gorrie G;Morrison I;Duncan C;Connelly P;Carod-Artal FJ;Davenport R;Reitboeck PG;Radunovic A;Srinivasan V;Preston J;Mehta AR;Leighton D;Glasmacher S;Beswick E;Williamson J;Stenson A;Weaver C;Newton J;Lyle D;Dakin R;Macleod M;Pal S;Chandran S
通讯作者：
Chandran S

National audit of cognitive assessment in people with pwMND A national audit of cognitive assessment in people with motor neurone disease (pwMND) in Scotland.

对 pwMND 患者认知评估的国家审计苏格兰对运动神经元疾病 (pwMND) 患者认知评估的国家审计。