Next-Generation Sensing For Human In Vivo Pharmacology- Accelerating Drug Development In Inflammatory Diseases

炎症性疾病是造成重大死亡、残疾和预后不良的原因，也是卫生服务的主要财政负担。尽管经过数十年的研究和数十亿英镑的研发投资，但没有靶向治疗方法可以调节中性粒细胞（一种参与炎症的关键细胞，也是肺癌周围的主要细胞，促进侵袭性和预后不良）。急性和慢性炎症性疾病，如哮喘、COPD和肺损伤是常见的，并且由于人口老龄化，其发病率和严重程度正在增加。因此，这项研究解决了现代药物开发面临的最大挑战之一，即开发人体检测系统的需求，这些系统为早期试验提供信心，以继续推进或终止药物开发计划。药物开发失败的一个主要原因包括历史上依赖于不能准确反映人类疾病的动物疾病模型。必须开发新技术，以了解和评估疾病和药物的有效性在体内原位在人类。这项研究建议将发展到接近临床准备，新的最先进的工程和数学方法，以提高从传感系统接收的数据的质量，该传感系统称为Kronoscan，能够在真实的图像和传感，使用一些世界上最快的检测器技术，以视频速率（>10fps）测量炎症生物标志物的荧光寿命数据，在新的维度上观察微观细节。荧光寿命克服了强度荧光成像的显著限制，并改善了定量。在患者中，我们将通过一种称为显微内窥镜的方法来实现这一点，该方法适用于影响肺部和胃肠道以及其他区域的疾病，我们可以将小型成像纤维深入组织。这种方法将与化学SmartProbes结合使用，当它们与发炎的细胞和组织相互作用时，它们会“发光”。该项目将与葛兰素史克合作进行，葛兰素史克将为临床试验提供开发中的“工具”化合物。GSK已经使用了其他成像方法，如CT扫描和PET成像，但将这种将高分辨率超灵敏显微成像添加到药物作用评估中的方法视为药物开发过程的主要补充，也是改善目前昂贵且生产率低下的药物开发途径的重要步骤。在爱丁堡大学与GSK部门合作，跨越信号处理、电气工程、化学和临床科学。该项目将基于Proteus跨学科的“枢纽”，以确保快速的产品开发。研究人员将花时间在爱丁堡和GSK的实验室，并安排一个开放的网络会议，以确保更广泛的参与。该提案中的科学家（研究人员共同研究者）将从网络和建立下一代体内药理学领域中受益匪浅。该研究的一个关键目标是为后续的临床和商业影响铺平道路，因此，用户（临床和监管）输入在技术开发过程中至关重要。该团队将利用现有的生产、监管和商业化支持能力和专业知识，加快开发。总之，该项目将产生：1）一个尖端的护理点技术平台，将帮助世界各地的药物开发人员，患者，医生和卫生保健工作者。 2)研究人员的职业发展。 3)开发一个全新的主题与“大制药”。4)一个可持续的网络，通过GSK的成像专营权传播技术。

Inflammatory diseases are responsible for significant death, disability and poor outcomes and are a major financial burden on the health service. Despite decades of research and billions of pounds of R&D investment, no targeted therapeutics exist that modulate neutrophils (a key cell involved in inflammation and also the major cell that surrounds lung cancers and promotes invasiveness and poor prognosis). Acute and chronic inflammatory diseases such as asthma, COPD and lung injury are common and are now increasing in incidence and severity due to the aging population. Hence, this research addresses, one of the biggest challenges facing modern drug development, the need to develop in-human assay systems that provide confidence in early trials to either continue progressing or terminating drug development programmes. A major cause for failures of drug development include the historical reliance on animal models of disease which do not accurately reflect human disease. It is essential to develop new technologies to understand and evaluate disease and drug effectiveness in vivo in situ in humans.This research proposal will develop to near-clinical readiness, novel state of the art engineering and mathematical approaches to improve the quality of the data received from a sensing system called Kronoscan which is able to image and sense in real-time at microscopic detail in new dimensions using some of the world's fastest detector technology, measuring fluorescence lifetime data of inflammatory biomarkers at video rate (>10fps). Fluorescence lifetime overcomes the significant limitations of intensity fluorescence imaging and improves quantification. In patients, we will enable this through a method called microendoscopy suited to diseases that affect the lungs and gastrointestinal tracts and other areas where we can pass small imaging fibres deep into tissue. This method will be coupled alongside chemical SmartProbes which "light" up when they interact with inflamed cells and tissues.The project will be undertaken in partnership with GlaxoSmithKline who will provide "tool" compounds in development for clinical trials. GSK already use other imaging methods such as CT Scans and PET Imaging but see this approach of adding in high resolution ultra sensitive microscopic imaging to the evaluation of drug action as a major addition to the drug development process and an essential step to improving a currently expensive and poorly productive drug development pathway.Work on the different elements needed to create this technology platform will be undertaken by investigators spanning signal processing, electrical engineering, chemistry and clinical science at the University of Edinburgh in collaboration with GSK divisions. This project will be based in the Proteus interdisciplinary "hub" to ensure rapid product development. The researchers will spend time in each others labs in Edinburgh and GSK as well as arranging an open network meeting to ensure broader engagement. The scientists (researcher co-investigators) in the proposal will benefit significantly from networking and establishing the area of next-generation in vivo pharmacology. A key ambition of the research will be to pave the way for subsequent clinical and commercial impact and as such user (clinical and regulatory) input will be paramount during the development of the technology. The team will leverage existing capability and expertise in manufacturing, regulatory and commercialisation support to expedite development. In summary, this project will generate; 1) A cutting edge point-of-care technology platform which will help drug developers, patients, doctors and health care workers throughout the world. 2) Career development of the researcher Co-Is. 3) Develop an entirely new theme with "Big Pharma". 4) A sustainable network to disseminate the technology through GSK's imaging franchise.