MRC Transition Support award CSF Kathryn Peall

MRC 过渡支持奖 CSF Kathryn Peall

基本信息

  • 批准号:
    MR/V036084/1
  • 负责人:
  • 金额:
    $ 61.75万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Fellowship
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

Aims of previous fellowshipThese included development of nerve cell models from tissue samples collected from patients diagnosed with Myoclonus Dystonia. Using these models, work was aimed at detailed understanding of the development and function of these nerve cells, particularly in relation to the neurotransmitter (chemical allowing communication between nerves) dopamine, how these changes might give rise to Myoclonus Dystonia and dystonic disorders.Background to the research and its importanceDystonia is one of the most common movement disorders, affecting 1 in 900 people, and is associated with significant lifetime disability for which there are no current effective treatments. This project is focused on Myoclonus Dystonia, an inherited form of dystonia and one of the few types caused by mutations to a specific gene (SGCE), making it an opportune disorder in which to study the underlying mechanisms of dystonia. Evidence from human brain imaging studies and animal models indicate that neurons in the cortex, as well as the communication (synapse) between mDA and MSNs form key areas of neuronal disruption in dystonia.Progress to dateThis has included developing three patient cell lines, as well as genetically correcting their SGCE mutations to provide a 'normal' (wildtype) genetically matched control (comparable) sample. To provide further evidence that the changes we're observing are due to SGCE mutations, we have genetically edited an embryonic stem cell line (often used in research), removing both copies of the SGCE gene. Studies of these cell lines have shown cortical neurons without SGCE to be more excitable (electrically active) and to have a more complex branching pattern, while the mDA and MSN suggest developmental changes in the relative proportions and nature of these cell types in the brain.Work planned for transition awardThe already developed mDA and MSN cell lines with undergo detailed electrical analysis on an individual cell level (patch-clamp technique) and as a network of cells (multi-electrode array). Chemical compounds that affect dopaminergic neurotransmission will be used to determine the effect of higher and lower levels of dopamine, as well as increasing and decreasing the activity of dopamine receptors and transporters. Changes in gene expression as a result of the SGCE mutations will be analysed using RNA-sequencing. This uses genetic material (RNA) taken from the cells at specific time points during their development and then evaluating the relative expression of these genes at each stage, indicating genes and gene pathways that are important in driving the mechanisms that cause Myoclonus Dystonia.Finally, both mDA and MSNs will be cultured together, allowing the different cell types to grow separately but form synapses (communicate) with each other. We will use combinations of the cell types, with and without SGCE mutations, to determine if the changes are due to differences within the neurons or are influenced by surrounding molecules. These detailed insights will improve our understanding of why dystonia symptoms arise, aiding the development of new therapies.Platform towards research leadershipThe Clinician-Scientist fellowship has provided me with a significant platform to begin to develop my own independent research group, as well as increase my recognition as an international leader within the dystonia research field. However, much of this credibility remains linked with my clinical expertise. This additional period of support would allow me to publish the stem cell work to date, as well as to complete and publish the remaining work, not only making a significant contribution to the field but also allowing recognition and development of my growing expertise in stem cell biology. This is essential in order to maximally capitalise on this work, through further grants and senior fellowship applications, as well as meaningful clinical applications.
以前的研究目标包括从诊断为肌阵挛障碍患者的组织样本中建立神经细胞模型。使用这些模型,工作旨在详细了解这些神经细胞的发育和功能,特别是与神经递质(允许神经之间通信的化学物质)多巴胺有关的多巴胺,以及这些变化如何导致肌阵挛障碍和肌张力障碍。研究背景及其重要性肌张力障碍是最常见的运动障碍之一,每900人中就有1人受到影响,并与严重的终生残疾有关,目前还没有有效的治疗方法。本项目的重点是肌阵挛障碍,这是一种遗传性肌张力障碍形式,是少数几种由特定基因(SGCE)突变引起的类型之一,使其成为研究肌张力障碍潜在机制的一种合适的疾病。来自人脑成像研究和动物模型的证据表明,皮质中的神经元,以及丙二醛和MSN之间的通讯(突触)构成了肌无力患者神经元破坏的关键区域。到目前为止,这方面的进展包括开发三个患者细胞系,以及从基因上纠正它们的SGCE突变,以提供一个“正常”(野生型)基因匹配的(可比较的)对照样本。为了进一步证明我们观察到的变化是由于SGCE突变造成的,我们对一株胚胎干细胞株(经常用于研究)进行了基因编辑,移除了SGCE基因的两个副本。对这些细胞系的研究表明,没有SGCE的皮质神经元更容易兴奋(电活动),并具有更复杂的分支模式,而MDA和MSN表明这些细胞类型在大脑中的相对比例和性质发生了发育变化。为过渡制定的工作计划已经开发的MDA和MSN细胞系将在单个细胞水平(膜片钳技术)和作为细胞网络(多电极阵列)进行详细的电分析。影响多巴胺能神经传递的化合物将被用来确定较高和较低水平的多巴胺的影响,以及增加和减少多巴胺受体和转运体的活性。由于SGCE突变导致的基因表达变化将使用RNA测序进行分析。这项技术使用在细胞发育过程中特定时间点从细胞中提取的遗传物质(RNA),然后评估这些基因在每个阶段的相对表达,指出在驱动Myoclonus Dystonius机制方面至关重要的基因和基因途径。最后,MDA和MSN将被一起培养,允许不同类型的细胞单独生长,但相互形成突触(通信)。我们将使用细胞类型的组合,有和没有SGCE突变,来确定这些变化是由于神经元内部的差异还是受到周围分子的影响。这些详细的见解将提高我们对肌张力障碍症状出现的原因的理解,有助于新疗法的开发。平台走向研究领导者临床医生-科学家联谊会为我提供了一个重要的平台,开始发展我自己的独立研究小组,并增加我作为肌张力障碍研究领域的国际领导者的认知度。然而,这种可信度在很大程度上仍然与我的临床专业知识有关。这段额外的支持期将使我能够发表迄今为止的干细胞工作,以及完成和出版剩余的工作,这不仅对该领域做出了重大贡献,而且使我在干细胞生物学方面日益增长的专业知识得到认可和发展。这是至关重要的,以最大限度地利用这项工作,通过进一步的赠款和高级奖学金申请,以及有意义的临床应用。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structural magnetic resonance imaging in dystonia: A systematic review of methodological approaches and findings.
Accelerometer-derived sleep measures in idiopathic dystonia: A UK Biobank cohort study.
  • DOI:
    10.1002/brb3.2933
  • 发表时间:
    2023-09
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Bailey, Grace A.;Wadon, Megan E. E.;Komarzynski, Sandra;Matthews, Clare;Davies, Elin Haf;Peall, Kathryn J. J.
  • 通讯作者:
    Peall, Kathryn J. J.
Use of remote monitoring and integrated platform for the evaluation of sleep quality in adult-onset idiopathic cervical dystonia.
  • DOI:
    10.1007/s00415-022-11490-4
  • 发表时间:
    2023-03
  • 期刊:
  • 影响因子:
    6
  • 作者:
    Bailey, Grace A.;Matthews, Clare;Szewczyk-krolikowski, Konrad;Moore, Peter;Komarzynski, Sandra;Davies, Elin Haf;Peall, Kathryn J.
  • 通讯作者:
    Peall, Kathryn J.
Adult-onset idiopathic dystonia: A national data-linkage study to determine epidemiological, social deprivation, and mortality characteristics.
成人发作的特发性肌张力障碍:一项国家数据链接研究,用于确定流行病学,社会剥夺和死亡率特征。
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Kathryn Peall其他文献

Parkinsonism, dementia and glucocerebrosidase mutations
  • DOI:
    10.1007/s00415-013-6923-1
  • 发表时间:
    2013-04-26
  • 期刊:
  • 影响因子:
    4.600
  • 作者:
    Kathryn Peall;Neil P. Robertson
  • 通讯作者:
    Neil P. Robertson
The TransEuro open-label trial of human fetal ventral mesencephalic transplantation in patients with moderate Parkinson’s disease
特兰斯欧洲开放性标签试验:人类胎儿腹侧中脑移植治疗中度帕金森病患者
  • DOI:
    10.1038/s41587-025-02567-2
  • 发表时间:
    2025-05-02
  • 期刊:
  • 影响因子:
    41.700
  • 作者:
    Roger A. Barker;Nicholas P. Lao-Kaim;Natalie Valle Guzman;Dilan Athauda;Hjalmar Bjartmarz;Anders Björklund;Alistair Church;Emma Cutting;Danielle Daft;Viswas Dayal;Stephen Dunnett;Amy Evans;Shane Grealish;Naomi Hannaway;Xiaoling He;Sam Hewitt;Zinovia Kefalopoulou;Philipp Mahlknecht;Antonio Martín-Bastida;Krista Farrell;Sarah Moore;Harry Bulstrode;Tagore Nakornchai;Jenny Nelander-Wahlestedt;Linnea Roupé;Gesine Paul;Kathryn Peall;Anne Rosser;Adriana Roca-Fernández;Sophie Rowlands;Anne-Marie McGorrian;Caroline Scherf;Ngoc Nga Vinh;Victoria Roberton;Claire Kelly;Mariah Lelos;Eduardo Torres;Kate Shires;Rachel Hills;Debbie Williams;Andreas-Antonios Roussakis;Krista Sibley;Pamela Tyers;Ruwani Wijeyekoon;Caroline Williams-Gray;Thomas Foltynie;Paola Piccini;Robert Morris;Stanley E. Lazic;Olle Lindvall;Malin Parmar;Hakan Widner
  • 通讯作者:
    Hakan Widner

Kathryn Peall的其他文献

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{{ truncateString('Kathryn Peall', 18)}}的其他基金

Determining the mechanisms of nigro-striatal dysfunction in SGCE mutation positive Myoclonus Dystonia using an iPSC-derived neuronal cell model
使用 iPSC 衍生的神经元细胞模型确定 SGCE 突变阳性肌阵挛肌张力障碍的黑质纹状体功能障碍的机制
  • 批准号:
    MR/P008593/1
  • 财政年份:
    2017
  • 资助金额:
    $ 61.75万
  • 项目类别:
    Fellowship

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