Isolation and characterization of novel microbial natural products that activate autophagy

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：自噬，字面意思是“自我吞噬”，是一个涉及细胞质物质降解的基本过程。这种自我平衡过程使细胞能够在条件不利时重新利用物质并产生能量，或者清除受损的细胞成分，或者清除过量产生的特定蛋白质。自噬功能障碍与许多疾病，如癌症、细菌和病毒感染有关。自噬活性随着年龄的增长而下降，因此与年龄相关疾病（如神经变性）的发展有关。因此，开发在生命过程中维持自噬活性的干预措施是重要的。链霉菌的天然产物产生许多具有治疗意义的代谢物。例如，雷帕霉素是链霉菌的天然产物，可诱导自噬。然而，雷帕霉素也有副作用，比如免疫抑制。因此，有必要确定可以大量生产但不缺乏这种副作用的其他天然化合物。这个项目的目的是分离和表征额外的新的天然化合物，可以激活自噬。具体来说，学生将利用一系列分析化学技术，包括LC-MS、HPLC和NMR光谱进行结构解析，并结合生物信息学预测感兴趣化合物的性质，从链霉菌制备的不同培养提取物中分离出新的天然化合物。然后，学生将测试这些化合物是否在人类神经退行性疾病的果蝇模型的幼虫和成年果蝇中激活自噬。亲自噬化合物刺激的分子和细胞途径将在哺乳动物组织培养细胞中进一步表征。

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:Autophagy, which literally means 'self-eating', is an essential process that involves the degradation of cytoplasmic material. This homeostatic process enables cells to reutilise materials and produce energy when conditions become unfavourable or to clear damaged cellular components or remove specific proteins if they are over-produced. Dysfunction in autophagy has been implicated in many diseases such as cancer and bacterial and viral infections. Autophagic activity declines with age and so has been associated with the development of age-related diseases, such as neurodegeneration. It is thus important to develop interventions that maintain autophagic activity through the life course. Natural products from Streptomyces bacteria produce many metabolites of therapeutic interest. For example, Rapamycin is a natural product from Streptomyces that induces autophagy. However, Rapamycin also has unwanted side effects such as immunosuppression. Thus, there is a need to identify additional natural compounds that can be produced in large quantities but without lack such side effects. The aim of this project is to isolate and characterize additional novel natural compounds that can activate autophagy. Specifically, the student will Isolate novel natural compounds from diverse culture extracts prepared using Streptomyces species using a range of analytical chemistry techniques including LC-MS, HPLC and NMR spectroscopy for structural elucidation, combined with bioinformatics to predict the nature of the compounds of interest. The student will then test if these compounds activate autophagy in larva and adult flies of Drosophila models of human neurodegenerative disease. The molecular and cellular pathways stimulated by pro-autophagic compounds will be characterized further in mammalian tissue culture cells.