MONOCYTE-BASED GENE THERAPY FOR ACUTE NEUTROPHIL-MEDIATED TISSUE INJURY

基于单核细胞的基因疗法治疗急性中性粒细胞介导的组织损伤

• 批准号: G0601401/1
• 负责人: Kev Dhaliwal
• 金额: $ 18.58万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0601401%2F1
• 关键词: MONOCYTE; BASED; GENE; THERAPY; ACUTE

This proposal is aimed at developing new treatments for lung diseases caused by excessive activation of cells used by the body to fight infection (neutrophils). In particular, a condition called adult respiratory distress syndrome is fatal in 40% of cases despite modern treatment, and survivors have considerable long-term problems.. The research involves manipulating another defence cell, the monocyte. Monocytes are recruited to inflamed sites alongside neutrophils and are amenable to therapeutic modification. I shall boost monocytes by providing extra copies of a protective gene called elafin. Elafin efficiently neutralises the main toxic product of neutrophils and makes monocytes switch off inflammation. I shall therefore insert elafin into human monocytes in order to reduce the toxic effects of ‘activated‘ neutrophils. I shall extend these findings to mice with the aim of reducing lung injury caused by neutrophils. These pre-clinical studies will lay the grounds for future clinical application in humans. Importantly, the principles of this proposal can be extended not only to other lung diseases associated with neutrophil malfunction (e.g. emphysema, bronchitis, cystic fibrosis) but to all causes of inflammation involving the neutrophil. The work therefore has potential implications for psoriasis, arthritis, peritonitis, and a host of other conditions

这一建议旨在开发新的治疗方法，以治疗由身体用于对抗感染的细胞（中性粒细胞）过度活化引起的肺部疾病。特别是，尽管有现代治疗，成人呼吸窘迫综合征仍有40%的病例是致命的，幸存者有相当大的长期问题。这项研究涉及操纵另一种防御细胞——单核细胞。单核细胞与中性粒细胞一起被募集到炎症部位，并且可以接受治疗修饰。我将通过提供一种叫做elafin的保护性基因的额外拷贝来增加单核细胞。Elafin有效地中和中性粒细胞的主要有毒产物，使单核细胞关闭炎症。因此，我将把elafin插入人类单核细胞中，以减少“活化”中性粒细胞的毒性作用。我将把这些发现扩展到小鼠身上，目的是减少中性粒细胞引起的肺损伤。这些临床前研究将为未来在人类中的临床应用奠定基础。重要的是，这一建议的原则不仅可以扩展到与中性粒细胞功能障碍相关的其他肺部疾病（如肺气肿、支气管炎、囊性纤维化），而且可以扩展到涉及中性粒细胞的所有炎症原因。因此，这项工作对牛皮癣、关节炎、腹膜炎和许多其他疾病有潜在的影响