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Metal-ion-based neurodegeneration: enabling techniques for understanding, detection, and treatment

基于金属离子的神经变性：理解、检测和治疗的支持技术

基本信息

批准号：
EP/K035193/1
负责人：
Joanna Collingwood
金额：
$ 12.73万
依托单位：
University of Warwick
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

来源：
https://gtr.ukri.org/projects?ref=EP%2FK035193%2F1
关键词：
Metal ion based neurodegeneration enabling

项目摘要

Many diseases of the human brain lead, over time, to degeneration of tissue and loss of function. By the time the disease is detected in an individual because of loss of function (whether cognitive or physical), extensive degeneration has in many instances already taken place. Reversing this degeneration presents an enormous challenge; the goal of this project is instead to focus on understanding factors that contribute to causing the degeneration, and to find ways of identifying the degeneration at an early stage in order to i) improve detection, and ii) offer new targets for effective treatment. A common theme linking many neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, Motor Neurone Disease, and Multiple System Atrophy, is that changes in the regulation of certain trace metals, and/or the proteins responsible for binding and utilizing these metal elements, are apparent. This can include accumulation of certain elements, such as iron, in specific regions of the brain. Our hypothesis is that these changes are disease-specific, and if better understood, may provide windows of opportunity for improved detection and treatment.Limiting factors affecting present work in this area include:i) the challenge of extrapolating findings from simple experiments in the laboratory to the complexity of the biochemical environment in the brain;ii) the challenge of accurate sensitive detection of trace metal elements in the brain - both for measurement in the living brain using clinical techniques, and for laboratory analysis of brain tissue. In the proposed research, a combination of experiments and computer-based modelling will be undertaken, in order to describe, predict, and test mechanisms of trace metal regulation that are anticipated to be affected in some of these neurodegenerative disorders. The models will be constructed using what is already known from experimental work, including published data from other research groups. In turn, as predictions are made by the models developed in this project, experiments will be designed and performed to test the predictions and update the models accordingly.Experiments to look at the interactions between metal-binding proteins and the trace metals that affect their aggregation, will be made more physiologically relevant by studying them in purpose-designed 'microfluidic' systems: experimental systems engineered to enable work with extremely small volumes (micro- or nanolitres) of sample. Microfluidic systems have three particular advantages in this context: i) they allow much smaller amounts of sample to be studied than would normally be the case, ii) they permit high-throughput testing of many experimental conditions for a single batch of protein which improves efficiency and reduces ambiguity in the results, and iii) the very small volumes and control of interfaces that can be achieved make it possible to mimic physiological conditions more accurately than has previously been possible.Very sensitive analysis of trace metals in tissues will be achieved in experiments using UK synchrotron facilities. These provide extremely bright beams of X-rays that can be focussed to micron or sub-micron diameters for mapping. The beams excite natural fluorescence signal from specific elements such as iron, copper, and zinc, enabling patterns of deposition to be mapped for each element even for trace concentrations of just a few parts per million. It is anticipated that the specific questions addressed in this project will help further our understanding of how iron affects the aggregation of a particular protein found in Lewy body pathology in Parkinson's disease, and will also enable progress in understanding how (and where) brain iron storage is affected in certain neurodegenerative disorders, to assess if there are sufficient differences for these diseases to be detected, and distinguished from each other, using Magnetic Resonance Imaging.

随着时间的推移，人类大脑的许多疾病导致组织退化和功能丧失。当一个人因为功能丧失（无论是认知功能还是身体功能）而被发现患有这种疾病时，在许多情况下已经发生了广泛的退化。逆转这种退化是一个巨大的挑战;该项目的目标是专注于了解导致退化的因素，并找到在早期阶段识别退化的方法，以便i）提高检测，和ii）提供有效治疗的新靶点。与许多神经退行性疾病如阿尔茨海默病、帕金森病、亨廷顿病、运动神经元病和多系统萎缩症相关的共同主题是某些微量金属和/或负责结合和利用这些金属元素的蛋白质的调节的变化是明显的。这可能包括某些元素的积累，如铁，在大脑的特定区域。我们的假设是，这些变化是疾病特异性的，如果更好地理解，可能会为改善检测和治疗提供机会窗口。影响这一领域目前工作的限制因素包括：i）从实验室的简单实验结果推断大脑中复杂的生化环境的挑战; ii）准确灵敏地检测大脑中的痕量金属元素的挑战--对于使用临床技术在活体大脑中进行测量，以及脑组织的实验室分析。在拟议的研究中，将进行实验和基于计算机的建模相结合，以描述，预测和测试痕量金属调节的机制，这些机制预计将在一些神经退行性疾病中受到影响。这些模型将使用从实验工作中已知的东西来构建，包括其他研究小组发表的数据。相应地，随着本项目中开发的模型做出预测，将设计和执行实验来测试预测并相应地更新模型。通过在专门设计的“微流体”系统中研究金属结合蛋白和影响其聚集的痕量金属之间的相互作用，将使实验更具生理相关性：实验系统设计用于处理极小体积（微升或纳升）的样品。在这种情况下，微流体系统具有三个特别的优点：i）它们允许研究比通常情况下少得多的量的样品，ii）它们允许对单批蛋白质的许多实验条件进行高通量测试，这提高了效率并减少了结果中的模糊性，以及iii）可以实现的非常小的体积和对界面的控制使得可以比以前更准确地模拟生理条件。组织中的金属将在使用英国同步加速器设施的实验中实现。这些提供了非常明亮的X射线束，可以聚焦到微米或亚微米直径的映射。这些光束激发来自铁、铜和锌等特定元素的自然荧光信号，从而能够绘制出每种元素的沉积模式，即使微量浓度仅为百万分之几。预计在这个项目中解决的具体问题将有助于我们进一步了解铁如何影响在帕金森病的路易体病理中发现的特定蛋白质的聚集，并且还将使理解铁如何影响帕金森病的蛋白质聚集的进展。脑铁储存在某些神经退行性疾病中受到影响，以评估是否存在足够的差异以检测这些疾病，用磁共振成像来区分它们。

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）

MRI evaluation of the relationship between R2, R2*, and tissue iron in the human basal ganglia

MRI 评估人基底节 R2、R2* 和组织铁之间的关系

DOI：
发表时间：
2014
期刊：
影响因子：
0
作者：
Collingwood JF
通讯作者：
Collingwood JF

Biogenic metallic elements in the human brain?

DOI：
10.1126/sciadv.abf6707
发表时间：
2021-06
期刊：
Science advances
影响因子：
13.6
作者：
Everett J;Lermyte F;Brooks J;Tjendana-Tjhin V;Plascencia-Villa G;Hands-Portman I;Donnelly JM;Billimoria K;Perry G;Zhu X;Sadler PJ;O'Connor PB;Collingwood JF;Telling ND
通讯作者：
Telling ND

Iron in the blood and the brain

血液和大脑中的铁