Exploration of Circadian Dysregulation in Cancer

项目概述：这个mrc资助的博士培训伙伴关系（DTP）将尖端的分子和分析科学与创新的数据分析计算方法结合在一起，使学生能够解决以假设为主导的生物医学研究问题。这是一个为期4年的课程，第一年包括一系列教学模块和两个基于实验室的研究项目，最终获得跨学科生物医学研究硕士学位。前两个学期包括一系列教学模块，让学生在多学科科学方面打下坚实的基础。学生还将参加一系列由分子、细胞和组织动力学、微生物学和感染、应用生物医学技术、人工智能和数据科学等领域的学术和行业专家主持的大师班。在第三学期和夏季学期，学生在他们选择的实验室进行两个为期11周的研究项目。项目：在地球上，环境每24小时都会发生重大而可预测的变化。大多数生物已经进化出生物定时机制，以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发生显著的每日调节。实验模型和流行病学数据显示，生物钟紊乱会增加患癌症的风险。例如，在小鼠乳腺癌模型中，每周进行一次颠倒的光/暗循环的小鼠，相当于上一个夜班，比对照组更早患上乳腺癌。然而，细胞时钟调控肿瘤发生的机制仍有待充分阐明。因此，我将在一个三维“活”基质——鸡胚胎CAM模型中研究昼夜节律系统对肿瘤发生的贡献。与塑料二维细胞培养板不同，CAM将为小鼠和人类肿瘤提供有节奏的环境，更接近于模拟体内情况。肿瘤微环境、CAM和胚胎时钟以及外部刺激（包括温度和光照）对肿瘤移植物的影响将通过多种方法进行评估。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为评估时钟功能提供连续的数据。同时，下一代测序将用于探测肿瘤及其微环境中不同细胞群分子钟的异质性。总之，这些方法将提供新的见解，将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.