Efficient, controlled delivery of synthetic anion carriers to epithelial cells for CFTR replacement therapy

高效、受控地将合成阴离子载体递送至上皮细胞，用于 CFTR 替代疗法

• 批准号: 2904232
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2904232
• 关键词: Efficient; controlled; delivery; synthetic; anion

The genetic disease cystic fibrosis (CF) is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The large number of variants and their complex effects on CFTR expression and function as an epithelial anion channel have stimulated the development of channel replacement therapeutic strategies for CF. In previous work, Professors AP Davis and DN Sheppard (University of Bristol) designed, synthesized and tested artificial anion transporters (anionophores) in artificial lipid membranes and cells. This work identified trans-decalin anionophores with promising biological activity, including potency and persistence without toxic effects. However, many anionophores with high activity in artificial lipid membranes are poorly deliverable to cells, arguing that they require specific drug delivery systems to achieve their therapeutic potential. This PhD project investigates the delivery of anionophores to epithelial cells using nanostructured drug-delivery platforms based on mesoporous silica particles developed by Dr AE Garcia-Bennett (Macquarie University). This innovative drug-delivery platform for anionophore delivery to CF epithelial cells will facilitate the translation of anionophores as a channel replacement therapy for CF. Moreover, the project provides excellent training in interdisciplinary research important for career development. It falls within the EPSRC Healthcare Technologies theme and Chemical biology and Biological Chemistry research area.

遗传疾病囊性纤维化（CF）是由囊性纤维化跨膜电导调节剂（CFTR）基因中的致病变异引起的。大量变体及其对CFTR表达和作为上皮阴离子通道功能的复杂影响刺激了CF的通道替代治疗策略的发展。在先前的工作中，AP Davis教授和DN Sheppard（布里斯托大学）在人工脂质膜和细胞中设计，合成和测试的人工阴离子转运蛋白（阴离子）。这项工作确定了具有有前途的生物学活性的跨核蛋白阴离子，包括效力和持久性而没有毒性作用。但是，许多在人工脂质膜中活性高的阴离子对细胞的递送不佳，认为它们需要特定的药物输送系统才能达到其治疗潜力。该博士学位项目研究了基于Ae Garcia-Bennett博士（Macquarie University）开发的纳米结构的药物递送平台向上皮细胞传递到上皮细胞。这个用于CF上皮细胞的阴离子传递的创新药物传递平台将促进与CF的通道替代疗法的转化。此外，该项目为跨学科研究提供了出色的培训，这对于职业发展很重要。它属于EPSRC Healthcare Technologies主题和化学生物学和生物化学研究领域。