How do different gene mutations cross talk with Tor and Notch signalling outputs of the Tuberous Sclerosis complex?

人类结节性硬化症复合体、TSC-1和TSC-2基因的突变导致一种严重且无法治愈的遗传疾病，这种疾病与肿瘤样生长和多个器官的细胞谱系缺陷有关。TSC调节mTor信号传导，tor抑制剂在抑制某些疾病表现方面部分有效。我们已经确定了一种新的TSC输出，通过Notch作用，它独立于Tor。在这个项目中，学生将使用果蝇模型遗传生物和多能干细胞技术以及CRISPR/CAS9基因编辑来阐明这种串扰发生的机制，并确定位于不同结构域的TSC-1或2疾病突变体如何影响不同的途径。这些结果将有助于对不同的患者突变进行分层，以进行潜在的靶向治疗，并映射到精准医学的主题上。在为期三个月的案例实习中，学生将与结节性硬化症协会合作，参与疾病生活史患者数据库的建设，学习慈善机构职能的不同方面，包括组织科学和非专业会议，筹款和撰写协会杂志和网站的非专业文章。该项目提供了一个独特的机会，将跨学科研究结合起来，同时与以疾病为重点的慈善机构进行互动和参与工作。

Mutations in human Tuberous sclerosis complex, TSC-1 and TSC-2 genes cause a serious and incurable genetically inherited disorder, which is associated with tumour-like growths with cell-lineage defects in multiple organs. TSC regulates mTor signalling and tor inhibitors are partially effective in supressing some disease manifestations. We have identified a novel output of TSC acting through Notch, which is independent of Tor. In this project the student will use Drosophila model genetic organism and pluripotent stem cell technology along with CRISPR/CAS9 gene editing to elucidate the mechanism by which this cross talk takes place and determine how TSC-1 or 2 disease mutants located in different domains affect different pathways. The results will contribute ability to stratify different patient mutants for potential targeted therapies and maps onto the theme of precision medicine. Working with the Tuberous Sclerosis Association during a three month CASE placement the student will participate in the construction of patient database of disease life histories, learn different aspects of the charities' functions, including organising scientific and lay meetings, fundraising and writing lay articles the association's magazine and website. This project offers a unique opportunity to combine interdisciplinary research while interacting with and participating in the work of a disease focussed charity.