High Resolution Imaging Using Transient Binders

使用瞬态粘合剂进行高分辨率成像

基本信息

  • 批准号:
    EP/W034735/1
  • 负责人:
  • 金额:
    $ 155.36万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Fellowship
  • 财政年份:
    2023
  • 资助国家:
    英国
  • 起止时间:
    2023 至 无数据
  • 项目状态:
    未结题

项目摘要

To better understand the behaviour of any disease and to develop treatment options for it, we need to understand processes occurring on the single molecule level as well as the cellular and tissue levels. However, biomolecules are highly dynamic and have complex structures which are difficult to observe simultaneously. Biomolecules such as DNA and proteins interact with many other molecules to perform their biological function. Exploiting these interactions with molecules such as drugs, to block or enhance function can be used to treat or prevent diseases. However, few experimental techniques can capture this information at the relevant spatiotemporal scales. This proposal will develop Localization Atomic Force Microscopy (LAFM) methods to enable near atomic resolution imaging of single biomolecules interacting with binding partners. By localizing the height signals as small molecules transiently bind to DNA or proteins, the resolution of the LAFM method will be increased and enable imaging of where drugs bind, how long they bind for and their effects on how the biomolecule functions. Additionally, the combined development of automatic spectroscopy methods will enable the measurement of binding kinetics on the microsecond to seconds timescale. This combination of high spatial and temporal resolution will allow new insight into protein and DNA including drug interactions, molecular mechanisms of disease and surface properties, opening opportunities to identify new drug molecules or targets.Technologies such as X-ray crystallography, surface plasmon resonance, isothermal titration calorimetry and more recently, cryo-electron microscopy and artificial intelligence have proven to be invaluable in understanding drug interactions with biomolecules in atomic detail. However, these technologies currently only provide static structures and ensemble averages of the most stable, lowest energy states across many molecules. To perform functions, proteins must undergo rapid dynamic changes; something which only a few techniques can currently capture across specific timescales with some constraints on protein size and order. My previous research has demonstrated the ability to obtain 4Å spatial resolution on single molecules with LAFM and a 10 microsecond time resolution using single point measurements with High-Speed AFM Height Spectroscopy. This, combined with my expertise in biophysics and high-speed AFM, will allow me to advance these techniques to further increase resolution and achieve quantitative binding kinetics with new LAFM methods.To develop my methodology, specifically designed DNA structures will be used as benchmark systems with fully predetermined binding site locations. A variety of target sites and binding molecules of varying size, affinity and binding mechanism will be explored to optimize localization algorithms, imaging parameters and conditions. These experiments will determine general rules governing resolution gains, localization precision at specific sites and the limits of detection for different binding interactions. Accurate and automated tip positioning at binding sites with predictive drift control will be developed for 10,000-fold increased time resolution for rapid binding kinetics to be measured using Height Spectroscopy. These newly developed techniques will then be used to image and measure kinetics of sugars to carbohydrate binding proteins often used by viruses, bacteria and other pathogens. Binding of drug fragments, peptides, and small proteins to 3 different proteins will be studied by the new technology to detect drug locations, kinetics and the resulting protein structural changes. In parallel with these experiments this fellowship will allow me to develop my leadership and research management skills, open-source software, and links to industry and academia, to ensure that the potential of these new methodologies are fully exploited.
为了更好地了解任何疾病的行为并开发治疗方案,我们需要了解在单分子水平以及细胞和组织水平上发生的过程。然而,生物分子是高度动态的,具有复杂的结构,很难同时观察。生物分子,如DNA和蛋白质,与许多其他分子相互作用,发挥其生物学功能。利用这些与药物等分子的相互作用来阻断或增强功能,可以用于治疗或预防疾病。然而,很少有实验技术能够在相关的时空尺度上捕捉到这种信息。这项提议将开发定位原子力显微镜(LaFM)方法,以实现单个生物分子与结合伙伴相互作用的近原子分辨率成像。通过在小分子与DNA或蛋白质瞬时结合时定位高度信号,LaFM方法的分辨率将提高,并能够成像药物结合的位置、结合的时间以及它们对生物分子功能的影响。此外,自动光谱方法的联合开发将使在微秒到秒的时间尺度上测量结合动力学成为可能。这种高空间和时间分辨率的结合将允许对蛋白质和DNA的新见解,包括药物相互作用、疾病的分子机制和表面性质,为识别新的药物分子或靶点提供了机会。X射线结晶学、表面等离子体共振、等温滴定热法以及最近的冷冻电子显微镜和人工智能等技术已被证明在从原子细节上了解药物与生物分子的相互作用方面具有非常重要的价值。然而,这些技术目前只提供了许多分子中最稳定、最低能量状态的静态结构和系综平均值。为了执行功能,蛋白质必须经历快速的动态变化;目前只有少数技术可以在特定的时间尺度上捕捉到这些变化,但对蛋白质的大小和顺序有一些限制。我之前的研究已经证明,使用LaFM可以在单分子上获得4?的空间分辨率,使用高速AFM高度光谱的单点测量可以获得10微秒的时间分辨率。这一点,再加上我在生物物理学和高速AFM方面的专业知识,将使我能够推动这些技术的发展,进一步提高分辨率,并使用新的LaFM方法实现定量结合动力学。为了发展我的方法学,专门设计的DNA结构将被用作具有完全预先确定的结合位点位置的基准系统。将探索各种不同大小、亲和力和结合机制的靶点和结合分子,以优化定位算法、成像参数和条件。这些实验将确定控制分辨率增益、特定位置的定位精度以及不同结合作用的检测极限的一般规则。将开发具有预测漂移控制的精确和自动结合部位的针尖定位,将时间分辨率提高10,000倍,以便使用高度光谱测量快速结合动力学。然后,这些新开发的技术将被用于成像和测量糖与碳水化合物结合蛋白的动力学,这些蛋白通常被病毒、细菌和其他病原体使用。这项新技术将研究药物片段、多肽和小蛋白与3种不同蛋白质的结合,以检测药物的位置、动力学和由此产生的蛋白质结构变化。在这些实验的同时,这一奖学金将使我能够发展我的领导和研究管理技能、开放源码软件以及与工业界和学术界的联系,以确保这些新方法的潜力得到充分开发。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
High-speed atomic force microscopy: extracting high-resolution information through image analysis.
高速原子力显微镜:通过图像分析提取高分辨率信息。
  • DOI:
    10.1007/s12551-023-01168-0
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Heath GR
  • 通讯作者:
    Heath GR
NanoLocz: Image analysis platform for AFM, high-speed AFM and localization AFM
NanoLocz:AFM、高速 AFM 和定位 AFM 的图像分析平台
  • DOI:
    10.1101/2023.11.23.568405
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Heath G
  • 通讯作者:
    Heath G
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

George Heath其他文献

Surface material of acoustic transmitters influences the inflammatory response of rainbow trout (Oncorhynchus mykiss) during long-term implantation.
声波发射器的表面材料影响虹鳟鱼(Oncorhynchus mykiss)在长期植入过程中的炎症反应。
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    1.8
  • 作者:
    George Heath;S. Semple;Tania Rodríguez;Sarah Hardy;Philip Harrison;I. Mulder;Michael Power;Brian Dixon
  • 通讯作者:
    Brian Dixon

George Heath的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似国自然基金

非小细胞肺癌Biomarker的Imaging MS研究新方法
  • 批准号:
    30672394
  • 批准年份:
    2006
  • 资助金额:
    30.0 万元
  • 项目类别:
    面上项目

相似海外基金

GrainQuest - using Artifical Intelligence and high resolution multimodal imaging to dissect the developmental and genetic basis of seed composition
GrainQuest - 使用人工智能和高分辨率多模态成像来剖析种子成分的发育和遗传基础
  • 批准号:
    2879608
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
    Studentship
Collaborative Research: Evaluating and parameterizing wind stress over ocean surface waves using integrated high-resolution imaging and numerical simulations
合作研究:利用集成高分辨率成像和数值模拟评估和参数化海洋表面波浪的风应力
  • 批准号:
    2319535
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
    Standard Grant
Collaborative Research: Evaluating and parameterizing wind stress over ocean surface waves using integrated high-resolution imaging and numerical simulations
合作研究:利用集成高分辨率成像和数值模拟评估和参数化海洋表面波浪的风应力
  • 批准号:
    2319536
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
    Standard Grant
Atomic resolution imaging using quantum sensors enabled by smart adaptive control
使用智能自适应控制启用的量子传感器进行原子分辨率成像
  • 批准号:
    2890685
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
    Studentship
Collaborative Research: High-resolution imaging of the Elgin-Lugoff earthquake swarm sequence and subsurface structures in South Carolina using a dense seismic nodal array
合作研究:使用密集地震节点阵列对南卡罗来纳州埃尔金-卢戈夫地震群序列和地下结构进行高分辨率成像
  • 批准号:
    2321095
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
    Standard Grant
Collaborative Research: High-resolution imaging of the Elgin-Lugoff earthquake swarm sequence and subsurface structures in South Carolina using a dense seismic nodal array
合作研究:使用密集地震节点阵列对南卡罗来纳州埃尔金-卢戈夫地震群序列和地下结构进行高分辨率成像
  • 批准号:
    2321094
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
    Standard Grant
Super-resolution imaging probe using novel chemical switch
使用新型化学开关的超分辨率成像探头
  • 批准号:
    23KK0106
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
    Fund for the Promotion of Joint International Research (International Collaborative Research)
Development of ultra-high resolution neutron imaging by quasi-direct detection using BGaN detector
利用 BGaN 探测器准直接探测开发超高分辨率中子成像
  • 批准号:
    23H00099
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Construction of high-resolution three-dimensional imaging techhnology using semiconductor optical phased array
利用半导体光学相控阵构建高分辨率三维成像技术
  • 批准号:
    22KJ0885
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Evaluation of photoreceptors health and function in diabetic retinopathy patients using a high-resolution retinal imaging device with controlled light stimulus
使用受控光刺激的高分辨率视网膜成像设备评估糖尿病视网膜病变患者的光感受器健康和功能
  • 批准号:
    10696696
  • 财政年份:
    2023
  • 资助金额:
    $ 155.36万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了