MiR-151a通过调控白介素12受体B2亚基（IL12RB2）参与特应性皮炎疾病发生的作用机制研究

Atopic dermatitis (AD) is a complex allergic skin disease, which is characterized by typically distributed eczematous skin lesions and intense pruritus. Dysregulated expression of microRNAs (miRNAs) in various tissues has been associated with a variety of disease. By employing HiSeq2000, we sequenced the miRNAs of peripheral white blood cells from AD patients and healthy controls. Nineteen differentially expressed miRNAs obtained by HiSeq2000 were further validated in an independent trial of 500 healthy donors and 500 atopic dermatitis patients using quantitative reverse transcription polymerase chain reaction assays. Through these analyses, we conclude that miRNAs can serve as potential biomarkers for the detection of atopic dermatitis. We also identified Interleukin 12 Receptor Beta 2 (IL12RB2) as one of the targets of miR-151a. IL12RB2 promotes the proliferation of T-cells as well as NK cells. IL12RB2 induces the promotion of T-cells towards the Th1 phenotype by strongly enhancing IFN-gamma production, which is associated with the pathogenesis of some allergic diseases such as asthma and AD. However, the role of miR-151a in AD needs to be further clarified, and the molecular mechanisms of miR-151a in the pathogenesis of AD remain unclear. In the present study, we will extensively investigate the role of miR-151a in the pathogenesis of AD at the molecular level, cell level and animal level. NC/Nga mice will be used as spontaneous AD model, and miR-151a knockout mice and IL12RB2 knockout mice will be used to establish induced AD model. Moreover, lentiviral system will be used to overexpress miR-151a or IL12RB2, or knockdown IL12RB2, in the peripheral blood cells and bone marrow cells of the mice. Overall, we aim to elucidate the pathogenic pathway of “miR-151a — IL12RB2 — Th1/Th2 cell differentiation — AD”, and provide additional insights towards the clinical treatment of AD.

特应性皮炎是一种以Th2细胞活化为主的慢性炎症性皮肤病。白介素12受体B2亚基（IL12RB2）通过诱导Th1型细胞因子IFN-γ的表达来维持Th1细胞的功能并抑制Th2细胞的分化。在本课题组的前期研究中，发现miR-151a的表达水平在特应性皮炎患者的外周血白细胞中显著升高，并已证实IL12RB2是miR-151a的靶基因，但miR-151a参与特应性皮炎发病过程的具体机制仍需进一步阐明。因此本项目拟在前期研究基础上，通过慢病毒在小鼠血液细胞及骨髓细胞中进行相关基因的过表达或敲减，并以NC/Nga小鼠、基因敲除小鼠作为主要的动物模型，分别从研究分子、细胞和整体动物水平探讨miR-151a通过调控IL12RB2的表达而参与特应性皮炎发病的具体作用机制。本项目旨在完善“miR-151a—IL12RB2—Th1/Th2细胞分化—特应性皮炎”这一致病途径，并为特应性皮炎的机制研究提供新的线索。

最近一些报导提示miRNA可以一种高度稳定且游离于细胞外的状态在血液中循环。miRNA的差异表达已在包括特应性皮炎在内的很多病理状态中被发现。特应性皮炎是一种以Th2细胞活化为主的慢性炎症性皮肤病。通过第二代深度测序技术，我们对特应性皮炎患者和健康人群中的血清miRNA进行测序，发现miR-151a的表达水平在特应性皮炎患者的外周血白细胞中显著升高，并已证实白介素12受体B2亚基（IL12RB2）是miR-151a的靶基因。IL12RB2通过诱导Th1型细胞因子IFN-γ的表达来维持Th1细胞的功能并抑制Th2细胞的分化，运用慢病毒在Jurkat细胞中过量表达miR-151a，也能检测到IL12RB2的表达下调，并伴随着各类Th1型细胞因子的表达下降。我的以上发现旨在完善“miR-151a—IL12RB2—Th1/Th2细胞分化—特应性皮炎”这一致病途径，并为特应性皮炎的机制研究提供新的线索。