Exploration of Circadian Dysregulation in Cancer

课程概述：这个由MRC资助的博士培训伙伴关系(DTP)将尖端分子和分析科学与数据分析中的创新计算方法结合在一起，使学生能够解决假设引导的生物医学研究问题。这是一个为期4年的课程，第一年包括一系列的教学模块和两个基于实验室的研究项目，这些项目导致了跨学科生物医学研究的硕士学位。前两个学期包括精选的教学模块，使学生能够在多学科的科学中获得坚实的基础。学生们还参加了由学术和行业专家主持的一系列大师课程，这些专家涉及分子、细胞和组织动力学、微生物学和传染病、应用生物医学技术以及人工智能和数据科学等领域。在第三学期和暑期，学生们在他们选择的实验室里进行两个为期十一周的研究项目。项目：在地球上，环境每24小时发生一次重大的、可预测的变化。大多数生物体都进化了生物计时机制，以便预测和应对昼夜带来的变化。这种所谓的生物钟导致超过三分之一的基因的表达每天都有显著的调节。在实验模型和流行病学数据中，扰乱生物钟已被证明会增加癌症风险。例如，在一个小鼠乳腺癌模型中，每周进行一个倒置的明/暗周期，相当于工作一个夜班的小鼠，比对照组更早患上乳腺癌。然而，细胞钟调控肿瘤发生的机制仍未完全阐明。因此，我将在一个3D“活”矩阵--鸡胚胎CAM模型中研究昼夜节律系统在肿瘤发生中的作用。与塑料2D细胞培养板不同，CAM将提供来自老鼠和人类肿瘤的肿瘤样本，具有节奏的环境，更接近体内的情况。将通过多种方法评估肿瘤微环境、CAM和胚胎钟以及包括温度和光暴露在内的外部刺激对肿瘤移植的影响。表达昼夜节律实时报告结构的鸡胚胎和肿瘤的生物发光成像将提供连续的数据来评估时钟功能。同时，下一代测序将用于探索肿瘤及其微环境中不同细胞群体的分子时钟的异质性。总之，这些方法将提供新的见解，有助于阐明有关生物钟在癌症中的作用的分子细节。

Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice. Project:On earth, the environment changes in a significant and predictable manner every 24 hours. Most organisms have evolved biological timing mechanisms in order to anticipate and respond to the changes brought by day and night. This so-called circadian clock leads to significant daily modulation in the expression of more than a third of genes. Disruption to the circadian clock has been demonstrated to increase cancer risk in experimental models and epidemiological data. For example, in a murine breast cancer model, mice subjected to one inverted light/dark cycle per week, equivalent to working one night shift, developed breast cancer sooner than the control group. However, the mechanism by which the cellular clock regulates tumourigenesis remains to be fully elucidated. Thus, I will investigate the contribution of the circadian timing system to tumorigenesis in a 3D "living" matrix, the chicken embryonic CAM model. Unlike a plastic 2D cell culture plate, the CAM will provide tumour samples from mouse and human tumours with a rhythmic environment, more closely mimicking the in vivo situation. The influence of the tumour microenvironment, CAM and embryo clock, and external stimuli including temperature and light exposure on the tumour grafts will be assessed via multiple approaches. Bioluminescence imaging of chicken embryos and tumours that express circadian real-time reporter constructs will provide continuous data to assess clock function. Meanwhile, next generation sequencing will be used to probe the heterogeneity of the molecular clocks of different cell populations within the tumour and its microenvironment. Together, these approaches will provide novel insights that will help elucidate molecular detail concerning the role of circadian clocks in cancer.