Developing a zebrafish launchpad for CART technology

为 CART 技术开发斑马鱼发射台

• 批准号: 2109249
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2109249
• 关键词: Developing; zebrafish; launchpad; CART; technology

Cytotoxic T lymphocytes (CTLs) are our bodies' most potent defence against the development of cancer. With correct priming, CTLs can also be prompted to attack established cancers. For CTLs to destroy their targets, they must express an antigen receptor (so-called T-cell receptor or TCR) recognising an antigen expressed on MHC by cancer cells. Tumours may not always express antigens or may otherwise interfere with the priming of CTLs. T cells engineered ex vivo to express chimeric antigen receptors (CARTs) represent an exciting application of synthetic biology that can circumvent the limitations of natural CTLs. The CAR comprises an extracellular antigen recognition domain capable of binding a surface antigen on the cancer cell (independently of MHC), fused to intracellular domains of signalling molecules which stimulate CTLs to proliferate and kill target cells (independently of cytokine stimulation by helper cells). If depletion of a cell lineage, such as melanocytes, can be tolerated then the antigen targeted needn't even be specific to cancer cells although it should be lineage restricted to avoid catastrophic organ damage. Alternatively, combinations of stimulatory and inhibitory receptors or partitioning stimulatory signals over multiple CARs (examples of logical gating) can still permit a relatively selective cytotoxic response. To date, clinical success with CARTs has been limited to a few cancer types, notably haematological malignancies, but it is a highly innovative approach, progressing rapidly. We have recently determined that melanoma in zebrafish is also under surveillance by T cells. This implies that zebrafish T cells also provide protection against cancer. Furthermore, there is significant sequence conservation for putative components of T-cell signalling pathways. We envisage zebrafish becoming a versatile in vivo test-tube for evaluating CART technology. Using highly efficient transgenic tools and established melanoma models, the successful candidate will work toward developing CART that recognise and selectively attack melanoma cells.

细胞毒性T淋巴细胞（CTL）是我们身体对抗癌症发展的最有效防御。通过正确的引发，CTL也可以被提示攻击已建立的癌症。对于CTL要破坏它们的靶标，它们必须表达抗原受体（所谓的T细胞受体或TCR），其识别癌细胞在MHC上表达的抗原。肿瘤可能并不总是表达抗原或可能以其他方式干扰CTL的引发。离体工程化的T细胞表达嵌合抗原受体（CART）代表了合成生物学的一个令人兴奋的应用，可以规避天然CTL的限制。CAR包含能够结合癌细胞上的表面抗原（独立于MHC）的细胞外抗原识别结构域，其与刺激CTL增殖并杀死靶细胞（独立于辅助细胞的细胞因子刺激）的信号传导分子的细胞内结构域融合。如果细胞谱系（如黑素细胞）的消耗可以耐受，那么靶向的抗原甚至不需要对癌细胞特异，尽管它应该是谱系限制的，以避免灾难性的器官损伤。或者，刺激性和抑制性受体的组合或在多个汽车上分配刺激信号（逻辑门控的实例）仍然可以允许相对选择性的细胞毒性应答。迄今为止，CART的临床成功仅限于少数癌症类型，特别是血液系统恶性肿瘤，但它是一种高度创新的方法，进展迅速。我们最近确定，斑马鱼的黑色素瘤也受到T细胞的监视。这意味着斑马鱼T细胞也提供抗癌保护。此外，T细胞信号传导途径的推定组分存在显著的序列保守性。我们设想斑马鱼成为一个多功能的体内试管评估CART技术。使用高效的转基因工具和已建立的黑色素瘤模型，成功的候选人将致力于开发识别和选择性攻击黑色素瘤细胞的CART。