分泌型miR-150对血管新生的作用的研究

Angiogenesis occurs in a number of normal physiological conditions including embryogenesis, reproduction and wound healing , as well as in many pathological processes including cancers and obesity-related disorders such as atherosclerosis and diabetes. In spite of sustained efforts, there are still gaps in our understanding of angiogenesis as it takes place in vivo. The molecular mechanism essential for the crosstalk between monocytes/macrophages and endothelial cells during angiogenesis remains to be fully elucidated.Recently we found that in human blood cells and cultured THP-1 cells, miR-150 was selectively packaged into microvesicles (MVs) and actively secreted. THP-1-derived MVs can enter and deliver miR-150 into human HMEC-1 cells, and elevated exogenous miR-150 delivered from MVs effectively reduced c-Myb expression and enhanced cell migration.In this study we try to identify the role of secreted miRNAs in angiogenesis.It would provide a novel miRNA-based therapeutic approach for disease treatment.

近年来，血管新生作为肿瘤、动脉粥样硬化等疾病的治疗的新的切入点，掀起了新的研究热潮。血管新生的机制已经基本阐明，促进血管内皮细胞的迁移是血管新生的关键环节，因此揭示影响内皮细胞迁移的因素对于开发新药用于抑制肿瘤的生长、促进组织损伤的修复等都有着积极作用。目前研究发现了VEGF等促进血管内皮细胞迁移的因素，但是血管内皮细胞在血管新生过程中的迁移机制还需要进一步阐明。我们近期发现分泌型miR-150能够促进血管内皮细胞的迁移，揭示了miRNA作用的新特点，以及对血管新生的研究展开了新领域。因此我们假设炎症状态下THP-1分泌的miR-150也能够促进血管新生。本项目旨在研究阐明分泌型miR-150对内皮细胞的迁移的促进也能够引起血管新生，并以此为切入点研究治疗肿瘤等血管新生相关疾病的新方法。

本课题从分泌型miRNA的角度出发，探索糖尿病、癌症等疾病在炎症状态下导致单核细胞分泌的miR-150的异常上升促进血管内皮细胞发生血管新生的影响，同时还发现了分泌的miR-150还可以调控肿瘤组织中VEGF的表达，进而更加促进了肿瘤内部的血管新生，从而促进肿瘤生长。同时本课题还发现通过微囊泡包裹miR-150 antisense能够有效的抑制血管新生和肿瘤生长，同样靶向修饰的微囊泡能够有效的将OPRM-siRNA递送到脑，治疗吗啡复吸，因而具有潜在的应用价值。因此，本课题从分泌型miRNA的角度出发，揭示了癌症的发病机制，同时探索了微囊泡作为药物递送系统的应用，为治疗肿瘤，毒品复吸等疾病提供了新的思路和手段，具有广泛的临床应用价值。