Ultrahigh sensitivity metabolomics: opening a window into the metabolic evolution of a sentinel invertebrate through the industrial revolution

超高灵敏度代谢组学：为了解工业革命中哨兵无脊椎动物的代谢进化打开一扇窗户

• 批准号: 1935325
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1935325
• 关键词: Ultrahigh; sensitivity; metabolomics; opening; window

METABOLOMICS is a proven technology for discovering mechanisms of how organisms respond to stress. However, the mass spectrometry methods employed do not yet provide sufficient analytical sensitivity to measure metabolites in the very small samples that are often encountered in environmental studies. Nanoscale liquid chromatography-mass spectrometry (nanoLC-MS) is applied extensively in proteomics - offering high sensitivity - but is not yet used in metabolomics due tomany technical challenges. Here we propose to partner with Thermo Fisher Scientific to establish and optimise novel nanoLC-MS methods to enable transformative investigations in environmental toxicology. Daphnia are freshwater invertebrates that play a central role in foodwebs and are widely studied in ecotoxicology. They can form dormant eggs that accumulate in sediments - which can hatch into functional animals many centuries later - allowing reconstruction of responses to past environmental change. This is termed resurrection ecology, and the current record isthe resurrection of 700 yr old Daphnia. The biochemical study of dormant eggs in sediment cores therefore offers a unique opportunity to investigate pollutant impacts on animal fitness from well before and throughout the industrial revolution, up to modern timescales of intensive agriculture and high pesticide usage. Yet Daphnia eggs weigh <1 mg, undetectable by current metabolomics technologies. Building on our decade-long track record in metabolomics, we propose to establish and optimise nanoLC-MS metabolomics technologies that are sensitive, reproducible and robust, and then apply these to discover the biochemical basis of Daphnia fitness through historically changing pollutant levels. Hence we will discover associations betweenenvironmental pollution and the health of this sentinel freshwater species.Our CASE PARTNER, Thermo Fisher Scientific (TFS), is a world leader in the development of nanoLC-MS and has identified metabolomics as a priority area. In 2013, TFS formed a Technology Alliance Partnership (TAP) with the University of Birmingham, the first such partnership within Europe. This proposal builds upon five existing iCASE awards with TFS as part of their commitment to graduate training. Collectively this team will provide SPECIALIST TRAINING: in nanoLC-MS, including unparalleled access to current and pre-released metabolomics technologies (at TFS); in metabolomics, environmental toxicology and analytical sciences (Viant lab; the largest group in environmental metabolomics nationally).TRANSFERABLE SKILLS will be taught at both Birmingham, through the extensive courses in the Biosciences Graduate Research School, and at TFS, including business awareness, project management and financial training. This training will be truly MULTIDISCIPLINARY to enrich the student experience. Furthermore the main supervisor is highly experienced,having completed 5 PhDs in the past five years and with 5 current students, several of which are/were NERC iCASE.

代谢组学是一种经过验证的技术，用于发现生物体如何应对压力的机制。然而，所采用的质谱法还没有提供足够的分析灵敏度来测量环境研究中经常遇到的非常小的样品中的代谢物。纳米液相色谱-质谱联用技术（nanoLC-MS）广泛应用于蛋白质组学，具有高灵敏度，但由于技术上的挑战，目前尚未应用于代谢组学。在这里，我们建议与Thermo Fisher Scientific合作，建立和优化新型nanoLC-MS方法，以实现环境毒理学的变革性研究。水蚤是淡水无脊椎动物，在食物网中发挥着核心作用，并在生态毒理学中得到广泛研究。它们可以形成休眠的卵，积累在沉积物中--这些卵可以在许多世纪后孵化成有功能的动物--从而重建对过去环境变化的反应。这被称为复活生态学，目前的记录是700岁水蚤的复活。因此，对沉积物芯中休眠卵的生物化学研究提供了一个独特的机会，可以调查从工业革命之前和整个工业革命期间，一直到现代集约化农业和农药大量使用的时间尺度，污染物对动物健康的影响。然而，水蚤卵的重量不到1毫克，目前的代谢组学技术无法检测到。基于我们在代谢组学方面长达十年的记录，我们建议建立和优化灵敏、可重复和稳健的nanoLC-MS代谢组学技术，然后应用这些技术通过历史上不断变化的污染物水平来发现水蚤适应性的生化基础。我们的合作伙伴赛默飞世尔科技（TFS）是纳米液相色谱-质谱（nanoLC-MS）技术的世界领先者，并将代谢组学确定为优先领域。2013年，TFS与伯明翰大学建立了技术联盟伙伴关系（TAP），这是欧洲第一个这样的伙伴关系。该提案建立在TFS现有的五个iCASE奖项的基础上，作为他们对研究生培训承诺的一部分。该团队将共同提供专家培训：nanoLC-MS，包括无与伦比的当前和预发布代谢组学技术（在TFS）;代谢组学，环境毒理学和分析科学（Viant实验室;全国最大的环境代谢组学小组）。转移技能将在伯明翰，通过生物科学研究生院的广泛课程，并在TFS，包括商业意识、项目管理和财务培训。这种培训将是真正的多学科，以丰富学生的经验。此外，主要主管经验丰富，在过去的五年中完成了5个博士学位，并有5名学生，其中几名是/是NERC iCASE。

项目成果

Confidence in metabolite identification dictates the applicability of metabolomics to regulatory toxicology

对代谢物鉴定的信心决定了代谢组学在监管毒理学中的适用性

• DOI: 10.1016/j.cotox.2019.03.006
• 发表时间: 2019
• 期刊: Current Opinion in Toxicology
• 影响因子: 4.6
• 作者: Malinowska J

Automated Sample Preparation and Data Collection Workflow for High-Throughput In Vitro Metabolomics.

• DOI: 10.3390/metabo12010052
• 发表时间: 2022-01-08
• 期刊: Metabolites
• 影响因子: 4.1
• 作者: Malinowska JM;Palosaari T;Sund J;Carpi D;Lloyd GR;Weber RJM;Whelan M;Viant MR
• 通讯作者: Viant MR

Integrating in vitro metabolomics with a 96-well high-throughput screening platform.

• DOI: 10.1007/s11306-021-01867-3
• 发表时间: 2022-01-09
• 期刊: Metabolomics : Official journal of the Metabolomic Society
• 作者: Malinowska JM;Palosaari T;Sund J;Carpi D;Bouhifd M;Weber RJM;Whelan M;Viant MR
• 通讯作者: Viant MR