Developing a decision-making toolkit for the personalised treatment of inflammatory bowel disease

开发炎症性肠病个性化治疗的决策工具包

• 批准号: 2265713
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2265713
• 关键词: Developing; decision; making; toolkit; personalised

Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD). CD is characterised by inflammation of the entire digestive tract, while inflammation is restricted to the large intestine in UC. About 300,00 people in the UK are affected by this debilitating disease. Furthermore, the severity and symptoms of IBD vary significantly between patients, and treatments often fail or are not sufficiently effective. Thus, despite the development of immunomodulatory drugs and biologic therapies, up to 80% of IBD patients will require surgery at some point in their lifetime.A precision medicine-based approach is crucial to improving the treatment of IBD in the future. Precision medicine considers an individual patient's genetic, environmental, and lifestyle factors prior to selecting an appropriate therapy. Using these principles, this project will attempt to identify novel biomarkers for IBD such that patients may be stratified, and clinicians can select appropriate therapies based on molecular profiling of a patient. Currently used biomarkers, such as C-reactive protein and calprotectin, are non-specific and cannot be used to stratify IBD patients. Thus, there is a need to identify novel biomarkers and develop technologies that can detect them, ideally in real-time and without the need for inconvenient stool samples or colonoscopies.Previous work by the Vendrell group has identified granzyme B as a novel biomarker of IBD. Granzyme B is a serine protease classically associated with its ability to induce cell death; however, in recent years it has been shown that granzyme B plays roles in many inflammatory diseases, from type 2 diabetes to psoriasis. In a large-scale proteomic screen, granzyme B expression levels were found to be increased in IBD patients, particularly those with UC. Following this discovery, the Vendrell group developed a fluorescent smartprobe that can specifically detect granzyme B activity. A key benefit of this smartprobe is that it measures the activity of granzyme B, not simple the amount of granzyme B present.The aim of this project is to develop a point-of-care technology using this smartprobe. The technology will help stratify patients based on expression of granzyme B, and aid clinicians in selecting an appropriate therapy. Importantly, the technology would detect granzyme B levels in blood, replacing inconvenient stool tests and invasive colonoscopies.The project is in collaboration with Genentech, who are currently developing the biologic etrolizumab, the efficacy of which appears to be linked to granzyme activity. I will complete an internship with the Early Biomarker Development team at Genentech at some point during the PhD.During this project, the smartprobe will be characterised and optimised such that granzyme B levels can be rapidly detected in a highly selective manner. Once achieved, the smartprobe will be used to examine granzyme B activity in clinical samples and investigate the role of granzyme B in pathogenesis.As part of the Precision Medicine DTP, I will be enrolled in a variety of courses that will provide me with skills to successfully execute the aims of the PhD project. In particular, I am developing skills in informatics and data analysis, with an emphasis on their roles in healthcare and medicine.

克罗恩病（CD）和溃疡性结肠炎（UC）是炎症性肠病（IBD）的两种主要形式。CD的特征是整个消化道的炎症，而UC的炎症仅限于大肠。在英国，大约有30万人受到这种使人衰弱的疾病的影响。此外，IBD的严重程度和症状在患者之间差异很大，治疗往往失败或不够有效。因此，尽管免疫调节药物和生物疗法的发展，高达80%的IBD患者将需要在其一生中的某个时候手术。精确的医学为基础的方法是至关重要的，以改善IBD的治疗在未来。精准医学在选择合适的治疗方法之前，会考虑个体患者的遗传、环境和生活方式因素。利用这些原则，该项目将尝试识别IBD的新生物标志物，以便对患者进行分层，临床医生可以根据患者的分子特征选择适当的治疗方法。目前使用的生物标志物，如C-反应蛋白和钙卫蛋白，是非特异性的，不能用于IBD患者的分层。因此，需要识别新的生物标志物并开发能够检测它们的技术，最好是实时检测，并且不需要不方便的粪便样本或结肠镜检查。Vendrell小组之前的工作已将颗粒酶B确定为IBD的一种新生物标志物。颗粒酶B是一种丝氨酸蛋白酶，通常与其诱导细胞死亡的能力相关;然而，近年来已显示颗粒酶B在从2型糖尿病到银屑病的许多炎性疾病中起作用。在大规模蛋白质组学筛选中，发现颗粒酶B表达水平在IBD患者中增加，特别是那些患有UC的患者。在这一发现之后，Vendrell小组开发了一种荧光智能探针，可以特异性地检测颗粒酶B的活性。这种智能探针的一个关键好处是它可以测量颗粒酶B的活性，而不是简单地测量颗粒酶B的含量。该项目的目的是使用这种智能探针开发一种即时技术。该技术将有助于根据颗粒酶B的表达对患者进行分层，并帮助临床医生选择适当的治疗方法。重要的是，该技术将检测血液中的颗粒酶B水平，取代不方便的粪便测试和侵入性结肠镜检查。该项目与基因泰克公司合作，后者目前正在开发生物etrolizumab，其疗效似乎与颗粒酶活性有关。我将在博士期间的某个时候完成在Genentech早期生物标志物开发团队的实习。在这个项目中，smartprobe将被表征和优化，以便可以以高度选择性的方式快速检测颗粒酶B水平。一旦实现，smartprobe将用于检测临床样本中的颗粒酶B活性，并研究颗粒酶B在发病机制中的作用。作为精准医学DTP的一部分，我将参加各种课程，这些课程将为我提供成功执行博士项目目标的技能。特别是，我正在发展信息学和数据分析方面的技能，重点是它们在医疗保健和医学中的作用。