Increasing capabilities for robust high-throughput clinical proteomics within the Centre for Proteome Research at the University of Liverpool

质谱仪(MS)是一项核心科学技术，用于生物医学研究的所有领域，以及在临床试验、外科手术和治疗分层决策之前，用于临床实验室的患者样本分析和基于生物标志物的筛选。它可以通过测量被称为离子的带电粒子的质荷比(或m/z)来非常准确地确定分子的质量。这样的测量使科学家能够表征和量化蛋白质(和其他生物分子)，并确定它们在不同条件下的组成和/或数量如何变化，包括与所有影响人类的主要疾病相关的蛋白质。质谱学非常灵敏，可以对正常的和疾病相关的蛋白质和多肽进行指纹识别，既可以预测疾病，也可以测量治疗反应。通过收购最先进的MS平台，我们的计划旨在取代利物浦大学蛋白质组研究中心(CPR)内老化的仪器，这是一个通过透明的成本回收结构管理的开放访问设施。所要求的平台旨在从血液等复杂生物样本中进行可重复性、健壮、灵敏和高通量的多肽定量，将显著扩大临床生物标记物发现的能力。该MS系统还将用于探索感染和癌症的耐药性机制，以及对患者进行治疗分层的先进筛选，包括通过基因分析确定的治疗分层。我们将利用成熟的成本回收模式，确保初始投资的寿命、性价比和最大影响，与利物浦内外的(临床)科学家合作，提供必要的专业知识，为所有MRC战略优先领域的项目生成定量蛋白质组学数据。例如，通过使用这项先进的技术来定义定义明确的模型系统和精心选择的临床队列中的蛋白质水平变化，我们将能够加快了解(除其他外)患者暴露于抗微生物药物(AMR)和靶向癌症治疗后发生的耐药性机制所需的时间，识别新诊断糖尿病患者中中风、慢性COVID和胰腺癌的生物标记物/预后标记物，以及定义解释个人对处方抗凝剂和抗精神病药物的个体反应的因素，这些药物在任何时候都有相当大比例的英国人口服用。利物浦共享研究设施(LIV-SRF)是CPR SRF的承保机构，设备将放置在我们的生物科学基础设施中，为利物浦内外最多的用户提供访问英国最好的研究设施的机会，包括为维护和开发像我们这样的“开放”和“透明”设施提供财政支持。除了促进获得尖端基础设施(以及最佳利用所需的专业知识)外，它还授予“准入赠款”，允许包括早期职业研究人员(ECR)在内的学者在赢得实质性同行审查资金之前利用这些设施支持新的研究想法。这些研究设施的使用加强了与NHS和行业等外部利益相关者的合作，使他们能够在学术环境中使用专业管理的技术外包一些分析。这种模式帮助推动了利物浦大学在MRC范围内基于蛋白质组学的研究的成功，但现在需要通过获得具有最先进能力的新设备来支持这一研究。

Mass spectrometry (MS) is a core scientific technology used across all areas of biomedical research, as well as in clinical laboratories for patient sample analysis and biomarker-based screening prior to decision making in clinical trials, surgical procedures and stratification for treatment. It can very accurately determine the mass of molecules by measuring the mass-to-charge ratio (or m/z) of charged particles called ions. Such measurements allow scientists to characterise and quantify proteins (and other biological molecules), and to determine how they change in composition and/or amount under different conditions, including proteins that are associated with all the major diseases that affect humans. Mass spectrometry is exquisitely sensitive, and can 'fingerprint' both normal and disease-associated proteins and peptides that can both predict disease and measure response to treatment.Through the acquisition of a state-of-the-art MS platform, our proposal seeks to replace aging instrumentation within the Centre for Proteome Research (CPR) at the University of Liverpool, an open-access facility managed through a transparent cost-recovery structure. The requested platform, which is designed for reproducible, robust, sensitive and high-throughput peptide quantification from complex biological samples such as blood, will significantly expand capability for clinical biomarker discovery. This MS system will also be used to explore mechanisms of drug resistance in infection and cancer alongside advanced screening for treatment stratification of patients, including those defined through genetic analysis. Using a well-established cost recovery model to ensure the longevity, value-for-money and maximal impact of the initial investment, we will work with (clinical) scientists both within and outside of Liverpool, providing the necessary expertise to generate quantitative proteomics data for projects across all the MRC strategic priority areas. For example, by using this advanced technology to define protein level changes in well-defined model systems and carefully selected clinical cohorts, we will be able to speed up the time required to understand (amongst other things) mechanisms of drug resistance that occur after patient exposure to anti-microbials (AMR) and targeted cancer therapies, identify biomarkers/prognostic markers for stroke, long COVID and pancreatic cancer in newly diagnosed diabetics, and define factors that explain inter-individual response to prescribed anti-coagulants and anti-psychotics, which are taken by a significant percentage of the UK population at any one time. Liverpool-shared research facilities (LIV-SRF), which underwrites the CPR SRF, where the equipment will be situated in our biosciences infrastructure, provides access to the very best UK research facilities for the maximal number of users, both inside and outside Liverpool, including financial support to maintain and develop 'open' and 'transparent' facilities such as ours. As well as facilitating access to cutting edge infrastructure (and the necessary expertise for optimal use), it also awards 'access grants', permitting academics, including Early Career Researchers (ECRs), to exploit these facilities to support new research ideas in advance of winning substantive peer-reviewed funding. Access to these research facilities enhances collaboration with external stakeholders such as the NHS and Industry, enabling them to outsource some of their analysis using professionally-managed technology in an academic setting. This model has helped drive the success of proteomics-based research at the University of Liverpool across the MRC remit, but which now needs to be bolstered by access to new equipment with state-of-the-art capabilities.