Isolation and characterization of novel microbial natural products that activate autophagy

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：自噬，字面意思是“自噬”，是一个涉及细胞质物质降解的基本过程。这种动态平衡过程使细胞能够在条件变得不利时重新利用材料并产生能量，或者在过度生产时清除受损的细胞成分或移除特定的蛋白质。自噬功能障碍与许多疾病有关，如癌症、细菌和病毒感染。自噬活动随着年龄的增长而下降，因此与与年龄相关的疾病的发展有关，如神经退化。因此，重要的是制定干预措施，在整个生命过程中保持自噬活动。链霉菌的天然产物会产生许多具有治疗意义的代谢物。例如，雷帕霉素是一种来自链霉菌的天然产物，可以诱导自噬。然而，雷帕霉素也有免疫抑制等不良副作用。因此，有必要确定更多的天然化合物，这些化合物可以大量生产，但不缺乏这种副作用。该项目的目的是分离和鉴定更多能够激活自噬的新型天然化合物。具体地说，学生将使用一系列分析化学技术从链霉菌物种制备的不同培养提取物中分离出新的天然化合物，包括LC-MS、高效液相色谱和核磁共振光谱，以确定结构，并结合生物信息学预测感兴趣的化合物的性质。然后，这名学生将在人类神经退行性疾病的果蝇模型的幼虫和成年果蝇身上测试这些化合物是否激活了自噬。在哺乳动物组织培养细胞中，将进一步描述由自噬前化合物刺激的分子和细胞途径。

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.