microRNA通过调控肺血管生成在支气管肺发育不良中的作用与机制研究

Bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disorder, the underlying pathogenesis is not fully understood. Studies have described disruption of vascular development in BPD. However, the molecular regulation of this BPD-associated dysangiogenesis remains undetermined. MicroRNAs are non-coding RNAs that are involved in regulating biological processes, including lung development and lung diseases. In this proposal, we will carry out the study at multiple levels, ranging from the molecular and cellular levels to the biological organisational (BPD newborn mice) level. Thus, various techniques will be performed, including microarray techniques, bioinformatics techniques, cellular and molecular techniques, angiography, ultrasound techniques and animal models. The first Specific Aim figures out the angiogenesis-associated signal transduction network modulated by microRNA involving of the development of BPD. The molecular mechanisms of the signal transduction network in the prevention of BPD-associated lung diseases are investigated in second Specific Aim. The third Specific Aim identifies microRNA from the signal net, which is associated with lung angiogenesis, and to investigat the effect of the unique microRNA on lung injury and repair during the development of BPD. New data from this proposal will provide a better understanding of the pathogenesis of BPD and thus may be helpful in developing an novel and effective treatment against BPD.

支气管肺发育不良（BPD）是一种多病因的慢性肺疾病，但发病机制却不清楚。近年研究发现，血管发育不良对BPD的发病有重要意义，但是与BPD相关的血管生成障碍的分子机制也不清楚。microRNA分子是一种非编码的单链小分子RNA，参与调控生物体内多种生物学过程，包括肺发育和肺部疾病。在本项目中，我们拟利用芯片、细胞分子生物学技术、生物信息学技术、血管造影技术、超声技术、动物模型等方法，从分子（过表达或干扰）、细胞（肺血管内皮细胞、肺上皮细胞）和整体（BPD新生小鼠）水平上进行不同层次的研究，构建出与BPD相关的由microRNA调控的血管生成信号转导网络，并研究其在BPD肺损伤、修复中的作用及其分子机制。最后，探寻出与肺血管生成特异相关的microRNA关键靶标，探索其在BPD肺损伤修复中的影响。本课题将更深入阐明BPD的发病机制，为BPD的干预治疗提供新的有效策略。

支气管肺发育不良（BPD）是一种多病因的慢性肺疾病，其发病机制却不清楚。近年研究发现，小血管发育不良对BPD的发病有重要意义。但是BPD相关的血管新生障碍的分子机制亦不清楚。microRNA分子是一种非编码的单链小分子RNA，参与调控生物体内多个生物学过程，包括肺发育和肺部疾病。本项目中，我们进一步收集及分析了BPD患儿病例资料，并利用芯片、分子生物学技术、生物信息学技术、细胞技术、血管造影技术、超声技术、动物模型等方法，从分子（过表达或干扰）、细胞（肺上皮细胞、肺血管内皮细胞）和整体（BPD新生小鼠）水平上进行不同层次的研究，构建并优化了与BPD相关的由microRNA调控的血管新生信号转导网络，并研究了该调控网络中关键microRNA及其靶基因在BPD肺损伤、修复中的作用。此外，本课题利用microRNA，研究了干细胞的血管形成能力及向肺泡上皮细胞分化过程中的作用及干细胞在BPD治疗中的安全性评价；并初步探索了siRNA、microRNA的相互作用对宿主细胞的影响。本课题深入阐明了BPD的发病机制，为探寻BPD干预治疗提供了新的有效策略，并为临床进一步采用miRNA新技术治疗肺部难治性疾病奠定了基础。