Developing Blood Cell Production Platforms for Therapeutic Applications

开发用于治疗应用的血细胞生产平台

• 批准号: 2282159
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2282159
• 关键词: Developing; Blood; Cell; Production; Platforms

Generation and modification of blood cells ex vivo or in vitro harbours a huge potential in cell based therapies and regenerative medicine. An important bottleneck in realising this potential is the difficulty in efficiently producing large amounts of blood products in vitro. One way to address this problem is to find new ways to effectively manipulate blood precursors and progenitors to create cell lines that can be amplified while still retaining their developmental potential. These cells could potentially represent an unlimited source of therapeutically relevant cell products such as modified natural killer cells, chimeric antigen receptor T-Cells, modified red blood cells, platelets or haematopoietic stem cells.The seminal demonstration that pluripotency can be induced by the ectopic expression of specific transcription factors has instigated a lot of interest in developing new strategies to manipulate the developmental potential of cells. Transcription factor directed reprogramming, trans-differentiation, or induced proliferation have been achieved through ectopic gene expression. Novel non-genetic methods, such as protein transduction or use of chemical compounds, have been demonstrated as potential alternatives to genetic modification producing similar results, establishing a clinical path for new discoveries in gene based cellular modulation strategies. This PhD project aims to develop new methods to produce large quantities of haematopoietic cells and differentiated haematopoietic progenitor cells through the establishment of novel blood cell lines. The project also aims to establish modified blood cell platforms for applications in advanced cellular therapies. An ideal target to induce proliferation of is the haemogenic endothelium (HE), which is a rare transient cell population generated during embryonic development, and the precursor to all adult blood cells including haematopoietic stem cells (HSCs). A HE cell line would be a powerful platform for the production of any adult blood lineage including HSCs and provide a tool for investigating the molecular pathways that drive and direct blood formation. The project aims to induce extensive proliferation of HE cells though ectopic gene expression, while maintaining the ability for these cells to transition from endothelial lineage cells to HSCs and their progeny. The potential of modifying these HE and blood cell lines to produce customized blood cell products will be explored with the ultimate goal of developing new potential cellular immunotherapies for the treatment of cancer and autoimmune diseases.

在体外或体外产生和修饰血细胞在细胞治疗和再生医学中具有巨大的潜力。实现这一潜力的一个重要瓶颈是难以在体外有效地生产大量血液制品。解决这个问题的一种方法是找到新的方法来有效地操纵血液前体和祖细胞，以创造出可以扩增的细胞系，同时仍保持其发育潜力。这些细胞可能代表着治疗相关细胞产品的无限来源，如修饰的自然杀伤细胞、嵌合抗原受体t细胞、修饰的红细胞、血小板或造血干细胞。特异转录因子的异位表达可以诱导多能性，这一开创性的证明激发了人们对开发操纵细胞发育潜力的新策略的兴趣。转录因子定向重编程、反式分化或诱导增殖已通过异位基因表达实现。新的非遗传方法，如蛋白质转导或化学化合物的使用，已被证明是基因修饰的潜在替代品，产生类似的结果，为基于基因的细胞调节策略的新发现建立了临床途径。本博士项目旨在通过建立新型血细胞系，开发大量生产造血细胞和分化造血祖细胞的新方法。该项目还旨在建立改良的血细胞平台，用于先进的细胞疗法。诱导造血内皮细胞（HE）增殖的理想靶点是造血内皮细胞（HE），它是胚胎发育过程中产生的一种罕见的瞬时细胞群，是包括造血干细胞（hsc）在内的所有成人血细胞的前体。一个HE细胞系将是一个强大的平台，用于生产任何成人血液谱系，包括造血干细胞，并为研究驱动和直接血液形成的分子途径提供工具。该项目旨在通过异位基因表达诱导HE细胞的广泛增殖，同时保持这些细胞从内皮系细胞转变为造血干细胞及其后代的能力。研究人员将探索修改这些HE和血细胞系以生产定制血细胞产品的潜力，最终目标是开发新的潜在细胞免疫疗法，用于治疗癌症和自身免疫性疾病。