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

这项提议旨在开发治疗肺部疾病的新疗法，这些疾病是由于身体用来对抗感染的细胞(中性粒细胞)过度激活而引起的。特别是，尽管进行了现代治疗，一种名为成人呼吸窘迫综合征的疾病在40%的病例中是致命的，幸存者有相当长的长期问题。这项研究涉及操纵另一种防御细胞--单核细胞。单核细胞被招募到中性粒细胞旁边的炎症部位，并接受治疗性修改。我将通过提供一种名为elafin的保护性基因的额外副本来提高单核细胞的数量。Elafin有效中和中性粒细胞的主要有毒产物，并使单核细胞关闭炎症。因此，我将把弹力纤维注入人类单核细胞中，以减少“激活的”中性粒细胞的毒性作用。我将把这些发现推广到老鼠身上，目的是减少中性粒细胞造成的肺损伤。这些临床前研究将为未来在人类身上的临床应用奠定基础。重要的是，这项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(例如肺气肿、支气管炎、囊性纤维化)，还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具有潜在的影响。

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