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、残疾和不良后果的原因，也是卫生服务的主要财政负担。尽管经过了数十年的研究和数十亿英镑的研发投资，但目前还没有一种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，促进侵袭性和不良预后）。急性和慢性炎症性疾病，如哮喘、慢性阻塞性肺病和肺损伤是常见的，现在由于人口老龄化，发病率和严重程度正在增加。因此，本研究解决了现代药物开发面临的最大挑战之一，即需要开发人体检测系统，为早期试验提供信心，从而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对动物疾病模型的依赖，这些模型不能准确地反映人类疾病。开发新技术来了解和评价疾病和药物在人体内的原位有效性是至关重要的。该研究计划将发展到接近临床的准备阶段，采用先进的工程和数学方法，以提高从Kronoscan传感系统接收到的数据的质量，该系统能够在新的维度上实时成像和感知微观细节，使用一些世界上最快的探测器技术，以视频速率（bbb10fps）测量炎症生物标志物的荧光寿命数据。荧光寿命克服了强度荧光成像的显著局限性，提高了定量。在病人身上，我们将通过一种叫做显微内窥镜的方法来实现这一点，这种方法适用于影响肺部和胃肠道的疾病，以及我们可以将小成像纤维深入组织的其他区域。这种方法将与化学智能探针相结合，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（GlaxoSmithKline）合作进行，后者将为临床试验提供正在开发的“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敏感显微成像加入药物作用评估的方法视为药物开发过程的重要补充，也是改善目前昂贵且低效的药物开发途径的重要一步。爱丁堡大学（University of Edinburgh）信号处理、电子工程、化学和临床科学领域的研究人员将与葛兰素史克（GSK）各部门合作，研究创建这一技术平台所需的不同要素。该项目将以Proteus跨学科“中心”为基础，以确保快速的产品开发。研究人员将在彼此位于爱丁堡和葛兰素史克的实验室呆上一段时间，并安排一次公开的网络会议，以确保更广泛的接触。提案中的科学家（研究人员和共同研究人员）将从网络和建立下一代体内药理学领域中获益良多。这项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，在技术开发过程中，用户（临床和监管）的投入将至关重要。该团队将利用现有的制造能力和专业知识，监管和商业化支持来加快开发。总之，这个项目将产生；1)一个尖端的即时护理技术平台，将帮助全世界的药物开发人员、患者、医生和卫生保健工作者。2)研究员Co-Is的职业发展。3)以“大型制药公司”为主题，打造全新主题。4)通过GSK的影像专营权，建立一个可持续的技术传播网络。

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.