Dynamic modelling of synthetically lethal pathways to enable the development of cancer therapeutics

在许多癌症中，驱动疾病的大多数遗传变化涉及受影响基因的功能丧失。这为利用癌细胞独特遗传属性的靶向治疗提供了挑战。合成致死（SL）是两个基因功能丧失导致细胞死亡的现象，而细胞可以耐受这些基因中任何一个单独功能丧失。合成致死性提供了一种治疗方法，使肿瘤抑制癌相关基因被靶向的靶向肿瘤抑制。博士生将加入珍珠生物信息学实验室，该实验室最近发表了计算方法，揭示了人类基因组中现有的SL基因对，并提出和验证了新的治疗SL基因对。该项目涉及确定治疗性合成致死基因对的途径，并为该途径建立动态计算模型。然后，学生将有机会与工业合作伙伴Oppilotech一起优化和测试该模型。在最后一年，目标的实验验证将在苏塞克斯大学基因组损伤稳定性中心的Hochegger实验室进行，学生将在那里接受实验方法（例如CRISPR/Cas9）的培训。它将验证计算方法，为生物学提供信息。研究结果将发表在同行评审期刊上。该项目有可能成为Oppliotech肿瘤学领域的药物发现项目，并最终对人类健康产生影响。

In many cancers the majority of genetic changes that drive the disease involve loss of function of the affected genes.This provides a challenge for targeted therapies that take advantage of the distinctive genetic attributes of cancer cells. Synthetic lethality (SL) is the phenomenon where loss of function in two genes causes cell death, whereas loss of function in either of these genes alone can be tolerated by the cell. Synthetic lethality provides a therapeutic approach that enables tumour suppressor cancer related genes to be targeted pharmacologically.The PhD Student will join the Pearl Bioinformatics Lab who have recently published computational methods that reveal existing SL gene pairs within the human genome and have proposed and validated novel therapeutic SL gene pairs. The project involves identifying a pathway for a therapeutic synthetic lethal gene pair and building dynamic computational models for that pathway. The student will then have the opportunity to optimise and test the model with the industrial partner Oppilotech.In the final year, experimental validation of the target will take place in the Hochegger laboratory in the Genome Damage Stability Centre at Sussex where the student will be trained in experimental methods (e.g. CRISPR/Cas9).We expect this project to have high impact. It will validate computational methodologies to inform biology. Findings will be published in peer reviewed journals. The project has the potential to lead into a drug discovery project within oncology at Oppliotech and ultimately impact on human health.