Engineering of human artificial chromosomes to decipher the mechanisms of chromosome instability-driven prostate cancer progression

人类人工染色体工程破译染色体不稳定驱动前列腺癌进展的机制

• 批准号: 2827672
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2827672
• 关键词: Engineering; human; artificial; chromosomes; decipher

Prostate cancer (PCa) is the most commonly diagnosed cancer in the UK and Europe, and responsible for close to 110,000 male deaths annually. Up to 20% of PCa cases present hallmarks of genomic instability characterized by chromosomal amplifications in the right arm of chromosome 8 (Chr.8q) -commonly associated with treatment resistance and poor survival rates. The Chr.8q region harbours the c-Myc oncogene whose copy gain was thought to be a strong candidate to explain the poor prognosis.To note, c-Myc copy number alterations (CNA) in minimally gained 8q regions can involve the co-amplification of up to 40-50 other genes, some acting as oncogenes involved in prostate, ovarian and breast cancer.4 Given the genetic complexity of chromosomal gains, the functional consequences of these amplified loci remain unknown due to the lack of cell models that can recapitulate the full genetic sequence, and order of that sequence, for use in cell models, both in vitro and in vivo. Therefore, this proposal aims to implement and engineer human artificial chromosomes (HAC) to reproduce the observed genetic aberrations in patients to decipher the mechanisms of chromosome amplifications-driven increased metastatic capability of cancer cells. This project has the potential to create a brand-new gold standard approach to model, characterise and screen for new drug candidate against genomic instability-related diseases.Objectives: Objective 1. Implementation of human artificial chromosomes mimicking Chr-8a amplification;Objective 2. Computational analysis, assembly and incorporation of the Chr-8q amplified regions;Objective 3. Deciphering the impact of copy gain on cancer progression

前列腺癌（PCa）是英国和欧洲最常见的癌症，每年造成近11万男性死亡。高达20%的PCa病例存在基因组不稳定的标志，其特征在于8号染色体右臂（Chr.8q）的染色体扩增-通常与治疗抗性和低存活率相关。Chr.8q区域含有c-Myc癌基因，其拷贝增加被认为是解释预后不良的强有力候选者。值得注意的是，在最小增加的8 q区域中的c-Myc拷贝数改变（CNA）可能涉及多达40-50个其他基因的共扩增，其中一些作为涉及前列腺癌、卵巢癌和乳腺癌的癌基因。4鉴于染色体增加的遗传复杂性，这些扩增的基因座的功能结果仍然是未知的，这是由于缺乏可概括完整遗传序列的细胞模型，以及该序列的顺序，用于体外和体内的细胞模型。因此，该提案旨在实施和工程化人类人工染色体（HAC），以再现患者中观察到的遗传畸变，从而破译染色体扩增驱动的癌细胞转移能力增加的机制。本项目有望为基因组不稳定性相关疾病的建模、预测和新药筛选提供一个全新的金标准方法。模拟Chr-8a扩增的人类人工染色体的实现;目标2。Chr-8 q扩增区域的计算分析、组装和掺入;目标3。解读拷贝增加对癌症进展的影响