Inhibition of monocyte production using siRNA against CD115 and M-CSF in autoimmune myocarditis

使用针对 CD115 和 M-CSF 的 siRNA 抑制自身免疫性心肌炎中的单核细胞产生

• 批准号: 234016914
• 负责人: Professor Dr. Florian Leuschner
• 金额: --
• 依托单位: Klinik für Kardiologie, Angiologie und Pulmologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234016914?language=en
• 关键词: Inhibition; monocyte; production; using; siRNA

Monocytes and macrophages are centrally involved in the progression of various diseases. The applicant was recently able to show that nanoparticle encapsulated siRNA against CCR2 prevents the accumulation of monocytes at the site of lesion. In so far unpublished experiments it was found that this newly developed nanoparticle also localizes to monocyte-producing myeloid progenitor cells. These myeloid progenitor cells, as well as monocytes express Colony Stimulating Factor 1 Receptor (CD115), which binds M-CSF, a cytokine essential for the production, proliferation and differentiation of monocytes.Aim of the here proposed project is to selectively reduce the production of monocytes by silencing CD115 in myeloid progenitors cells and monocytes with nanoparticle encapsulated siRNA. Secondly, with monocytes being main producers of M-CSF themselves, an additional siRNA will be explored to block the synthesis of the cytokine. Following ex vivo- and in vivo- validation experiments it will be tested in the mouse model of autoimmune myocarditis if reduced monocyte production through siRNA-nanoparticles results in a reduction of cardiac inflammation and impacts the outcome of disease.This new approach could facilitate the exclusive modulation of the myeloid cell lineage and offer new therapeutic options in immune therapy.

单核细胞和巨噬细胞主要参与各种疾病的进展。申请人最近能够证明纳米颗粒包封的针对CCR 2的siRNA防止单核细胞在病变部位的积累。在迄今为止未发表的实验中，发现这种新开发的纳米颗粒也定位于产生单核细胞的骨髓祖细胞。这些髓系祖细胞以及单核细胞表达集落刺激因子1受体（CD 115），其结合M-CSF，M-CSF是单核细胞的产生、增殖和分化所必需的细胞因子。其次，由于单核细胞本身是M-CSF的主要生产者，将探索另外的siRNA来阻断细胞因子的合成。在体外和体内验证实验之后，将在自身免疫性心肌炎的小鼠模型中测试通过siRNA纳米颗粒减少单核细胞产生是否会导致心脏炎症的减少并影响疾病的结果。这种新方法可以促进骨髓细胞谱系的排他性调节，并为免疫治疗提供新的治疗选择。