BCL6介导的"transrepress"转录调控模式及其在肺损伤和炎症中的作用机制研究

Inflammation induced by infection and injury is considered to be one of the effective mechanisms to maintain the tissue homeostsis against injurious insults, while uncontrolled inflammatory signalings and abnormal gene expression lead to varieties of diseases. The regulatory mode of transpressing, composed of the key transcritical factor and other related molecules emergs as a novel form of transcrptional regulation. Using murine lung injury and inflammation models, we found that BCL6 (B-cell lymphoma 6) was specifically induced upon the injury and inflammatory triggers. Decrease of BCL6 levels however promoted the production of proinflammatory cytokines and chemokines, which demonstrated to be regulated by the gene transcription. Further studies will focus on BCL6-mediated regulation on inflammatory signal transductiona and gene expression. The relationship between BCL6 and other regulators, BCL6, BcoR, HDAC3 and PU.1 respectively will be investigate in the context of lung injury and inflammatio, and their effects on the activaion, proliferation and apoptosis of inflammatory cells as well as pulmonary epithelial cells will be identified with loss-or-gain techniques. Furthermore, utilizing cell-target DN(donminant negative)-BCL6 transgene mice system, we endeavor to establish the correlations between BCL6-mediated regulatory and the development of lung injury and inflammation, which might provide hints for the mechanistic studies of inflammatoy lung diseases, as well as potent molecular target for the prevention and treament of the diseases.

感染和损伤引起的炎症是机体维持自稳的重要机制，而过度的炎症应答和基因表达异常可引发疾病发生，以关键转录因子和相关分子共同构成的"transrepressing"模式为基因转录调控提供了一种新范式。利用小鼠肺损伤和炎症模型，我们发现核转录因子B细胞淋巴瘤因子6（B-cell lymphoma 6, BCL6）呈特异性高表达，下调该分子则促进炎性细胞因子和趋化因子增加，且该作用与转录调控密切相关。进一步研究将分析BCL6参与炎症信号转导及基因表达调控的分子机制，确立肺损伤和炎症背景下BCL6与BcoR、HDAC3、PU.1等调控子的相互作用，结合loss-or-gain手段分析该作用对炎性和肺上皮细胞活化、增殖、凋亡的影响；并通过DN(donminant negative)-BCL6靶向转基因小鼠体系，建立 BCL6介导的转录调控模式与肺损伤-炎症之间的联系，为相关疾病研究提供线索和分子靶标。

“感染-炎症-损伤-修复”各环节的有序调控是保证机体组织自身稳定的重要保证。非可控的肺部炎症和损伤是造成急性呼吸道窘迫综合症、慢性阻塞性肺病、肺纤维化和肺癌等疾病发生的重要原因，目前人们对其机制的了解仍不深入。本项目通过分子¬-细胞-整体水平的研究，发现并确认了肺损伤和炎症进程中Bcl6的表达规律及其调控模式，系统地阐明了Bcl6参与肺部炎症和损伤调控的分子免疫学机制：发现了Bcl6 通过调节巨噬细胞极性转化调控肺部炎症和损伤的作用机制；揭示了Bcl6通过形成与NcoR2和HDAC3共分子参与机体抗病毒免疫和炎症反应的新模式；探究了Bcl6及相关分子在肺上皮细胞恶性转化和炎症细胞免疫代谢中的调控作用及机制。在此基础上，通过体内试验进一步验证了Bcl6介导的信号转导调控模式与肺损伤-炎症-恶变之间的内在联系，确立了Bcl6调控的关键环节和作用靶点。这些研究成果为探究炎症、免疫、感染和细胞恶变过程中的细胞分子机理提供了新思路，也为肺部损伤和炎症相关疾病的诊疗提供了潜在靶标和干预策略。