WOrM Drug Models: Whole Organism Metabolomic Drug Models to improve holistic understanding of therapeutic performance

CDT主题对齐：预测性药物科学、药物工艺工程和复杂产品表征该项目旨在建立秀丽隐杆线虫作为模型系统，以确定药物对全生物体代谢组学全球变化的影响，以提高治疗性能。背景技术背景：代谢组学被认为是生物体的生理状态和表型的功能读数，可以通过药物治疗显着改变。人体代谢组学的有效建模具有挑战性。这是因为人类是大型复杂的动物，尚未完全了解，并且可能在科学和社会经济方面都具有挑战性。因此，国际上有一股强烈的动力来取代、减少和完善动物在研究中的使用，以便将这一宝贵资源保留给最强的治疗候选药物，同时也提供一种机制来改善那些在早期开发阶段失败的治疗方法。考虑到这一点，需要开发创新的解决方案或重新利用现有的模型，以提供对治疗性能的关键见解。一个很好的潜在解决方案的例子是模式生物C。优雅C.秀丽线虫是一种自由生活的线虫，是地球上了解最全面的动物。这是因为它的尺寸小（<1 mm），世代时间短（<3天），光学透明度，遗传变异的可用性和内政部动物法规的排除。迄今为止，已获得了C. elegans已经被绘制出来了。然而，目前还没有现成的代谢信息的C。优雅实验方法：该项目将利用诺丁汉大学药学院和世界领先的分析生物科学中心（CAB）和纳米与微米研究中心（nmRC）的分析设施，填补整个生物体代谢组学对药物的反应方面的重要知识空白。CAB是高分辨率超高效液相色谱-串联质谱（UHPLC-MS/MS）的所在地。将使用UHPLC-MS/MS来解读挑战广泛使用的药物的线虫匀浆的代谢组学特征，以及关于对生理状态影响的成熟文献（阿替洛尔、对乙酰氨基酚、氟西汀、奥美拉唑和辛伐他汀）。这将为具有已知药物活性的治疗剂提供校准的代谢组学结果。线虫也将受到下一代治疗药物“反向前药”的挑战，这种药物通过引入电活性来自我聚合以阻止癌症生长。校准药物样品的代谢组将为下一代治疗的生理状态提供重要的见解，并提供改善性能的途径。nmRC拥有世界上唯一的学术性3D-OrbiSIMS，能够进行高空间和化学分辨率的三维质谱分析。从LC-MS鉴定的关键代谢组学变化将与3D-OrbiSIMS进行空间协调。这个科学的第一次将被用来产生一个“谷歌街景”的整个有机体代谢组学的C。优雅这将是一个宝贵的资源，研究人员，以提高他们的理解的生理状态蠕虫WORM和那些进一步的知识，C。作为复杂哺乳动物生物化学的模型。影响：这一多学科项目将提高对治疗对代谢途径的影响的理解，并将有助于生产新的和改进的药物，以预防和治疗疾病，如癌症。它还将为博士候选人提供多样化的培训机会。在经验丰富的监督团队的支持下，所进行的研究将为建立新的和改进的药物输送模型和分析铺平道路。

CDT theme alignment: Predictive Pharmaceutical Sciences, Pharmaceutical Process Engineering and Complex Product Characterisation This project will aim to establish Caenorhabditis elegans as a model system to determine the influence of pharmaceuticals on global shifts in Whole Organism Metabolomics, to improve therapeutic performance. BACKGROUND: Metabolomics is considered as the functional readout of the physiological state and phenotype of an organism, which can be significantly transformed by drug treatment. Effective modelling of metabolomics in humans is challenging. This is because humans are large complex animals, which are not completely understood and can be both scientifically and socio-economically challenging to characterise. Therefore, there is a strong international drive to replace, reduce and refine the use of animals in research so that this precious resource is reserved for the strongest therapeutic candidates, whilst also providing a mechanism to improve those therapeutics that fail at early-stage development. Bearing this in mind there is a need to develop innovative solutions or repurpose existing models that can provide key insights into therapeutic performance. An excellent example of a potential solution is the model organism C. elegans. C. elegans, a free-living nematode, is the most completely understood animal on the planet. This is due to its small size (<1 mm), short generation time (<3 days), optical transparency, availability of genetic variants and exclusion from Home Office animal regulations. To date, the complete genome, proteome and connectome for C. elegans have been mapped. However, currently there is no readily available metabolic information on C. elegans. METHOD: This project will fill the important knowledge gaps in whole organism metabolomics in response to drugs by harnessing the School of Pharmacy's & University of Nottingham's world leading analytical facilities of the Centre for Analytical Bioscience (CAB) and Nanoscale & Microscale Research Centre (nmRC). The CAB is home to a high-resolution ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). UHPLC-MS/MS will be used to decipher metabolomic profiles of nematode homogenates challenged to widely used pharmaceuticals, with well-established literature on influence on physiological state (atenolol, acetaminophen, fluoxetine, omeprazole and simvastatin). This will provide a calibrated metabolomic outcome to therapeutics with known pharmaceutical activity. Nematodes will also be challenged to next generation therapeutics, "reverse prodrugs," which self-polymerise through the introduction of electrical activity to stop cancer growth. The metabolome of the calibrated drug samples will provide an important insight to the physiological state of next-gen therapies and provide pathways to improve performance. The nmRC hosts the world's only academically situated 3D-OrbiSIMS, capable of high spatial and chemical resolution three-dimensional mass spectrometry. The key metabolomic shifts identified from LC-MS will be spatially coordinated with 3D-OrbiSIMS. This scientific first will be used to produce a "Google street view" of Whole Organism Metabolomics for C. elegans. This will be a valuable resource for researchers to improve their understanding of the physiological state of WOrMs and those furthering the knowledge of C. elegans as a model for complex mammalian biochemistry. IMPACT: This multidisciplinary project will improve the understanding of the influence of therapeutics on metabolic pathways and will contribute to the production of new and improved drugs to prevent and treat diseases, such as cancer. It will also provide diverse training opportunities for the PhD candidate. With support form the experienced supervisory team the research conducted will pave-the-way towards establishing new and improved models and analytics for drug delivery.