PPARγ与lncRNA PACER相互抑制的分子机制及其在脓毒症急性肺损伤中的作用研究

Acute lung injury (ALI) is a lung disease with high morbidity and mortality, which inflammation is one of the main causes. Therefore, effective anti-inflammatory therapy is one of the important strategies to control ALI. Recently, the function of long noncoding RNA (lncRNA), which is closely related to inflammatory response of ALI, has been received growing concern. Our preliminary data showed that lncRNA PACER is closely related to ALI caused by sepsis, and PACER can be significantly down-regulated by the anti-inflammatory nuclear receptor PPARγ. Meanwhile, we found that the PACER can also negative feedback to inhibit PPARγ. Furthermore, the molecular mechanism of mutual inhibition was discussed and several innovative findings were got. Based on our preliminary discoveries, we hypothesize that PPARγ may inhibit lncRNA PACER by directly binding to PACER promoter region, and play a protective role for ALI. While, PACER may increase ATF3 by adsorption of mir-7 and negative feedback to inhibit PPARγ, which play a promoting role in ALI. In the present project, we will deeply analyze the molecular mechanism regarding the reciprocal inhibition between PPARγ and PACER, and elucidated its important role in ALI inflammatory response. The expected results of this project may provide scientific evidences for exploring a new strategy for the clinical treatment of ALI by targeting the reciprocal inhibition loop between PPARγ and PACER.

急性肺损伤（ALI）是发病率和死亡率极高的肺部疾病，炎症是导致ALI主要因素之一。因此，有效地抗炎治疗是防治ALI的重要策略之一。近年，与炎症反应密切相关的长链非编码RNA（lncRNA）在ALI中的作用倍受关注。我们发现：lncRNAPACER与脓毒症所致的ALI密切相关，抗炎核受体PPARγ可显著下调PACER；而PACER又可负反馈抑制PPARγ，进而对二者相互抑制的分子机制进行探讨且获得创新发现，据此提出如下假设：PPARγ可能通过直接结合于PACER启动子区，下调PACER，对ALI发挥保护作用；而PACER可能通过吸附miR-7上调ATF3进而负反馈抑制PPARγ，对ALI发挥促进作用。本项目将深入解析PPARγ与PACER相互抑制环路的存在及形成的分子机制，并阐明其在ALI炎症反应中的重要作用，从而为探索以PPARγ与PACER相互抑制环路为靶标的ALI临床治疗提供新的策略。

急性肺损伤（ALI）是发病率和死亡率极高的肺部疾病，巨噬细胞介导的炎症反应是导致ALI主要因素之一。项目拟研究巨噬细胞内PPARγ与lncRNA PACER相互抑制环路的存在及形成的分子机制，并阐明其在ALI炎症反应中的重要作用，从而为探索以PPARγ与lncRNA PACER相互抑制环路为靶标的ALI临床治疗提供新的策略。研究结果发现lncRNA PACER在巨噬细胞及小鼠脓毒症急性肺损伤模型中上调。LPS作用后，促炎因子水平升高，miR-124 mRNA表达降低。敲低巨噬细胞lncRNA PACER能抑制炎症，上调miR-124 mRNA表达，上调PPARγ蛋白表达及减轻ALI小鼠肺部炎症。在PPARγ敲除鼠模型中，LPS诱导ALI后，敲除组炎症加重，PPARγ 激动剂处理后炎症无缓解。在野生型小鼠中，LPS诱导ALI后，PPARγ 激动剂处理后炎症缓解。 激活PPARγ可以促进miR-124的表达且下调其靶基因TRAF6水平。PPARγ通过与miR-124启动子的结合促进miR-124的转录。此外研究还发现ALI模型中， PPARγ 激动剂预处理后自噬水平上调，肺部炎症减轻，根据此现象及靶标分子，研究了利用DNA纳米材料干预策略防治ALI。复合DNA纳米材料能协同促进巨噬细胞自噬，促进巨噬细胞往抗炎型（M2型）转化，从而治疗ALI。目前的研究明确了PPARγ 与 lncRNA PACER在调节脓毒症致 ARDS中的重要作用。阐明了PACER通过调控PPARγ以及miR-124进而发挥调控炎症反应的可能机制。同时利用新型DNA纳米材料进行干预，为脓毒症致 ARDS提供潜在纳米治疗策略。