长链非编码RNA（LncRNA-AD1）通过调控胸腺基质淋巴生成素而参与特应性皮炎发病的作用机制研究

Atopic dermatitis (AD) is a complex allergic skin disease. Thymic Stromal Lymphopoietin (TSLP) is an important molecule that initiates the Th2-mediated allergic inflammation such as AD. The expression of TSLP was significantly increased in the skin tissue of AD patients. However, it ramains unclear how the expression of TSLP was regulated. In our previous study, we found that LncRNA-AD1, which is a long non-coding RNA (LncRNA), might be one of the important factors that regulate the expression of TSLP. The expression pattern of LncRNA-AD1 was positively correlated with that of TSLP. Our preliminary data also showed that miR-142 might serve as a mediator in the LncRNA-AD1 and TSLP regulatory network. TSLP is a potential target of miR-142, and LncRNA-AD1 could compete with TSLP to bind miR-142. High levels of LncRNA-AD1 would absorb miR-142, resulting in the decrease of free miR-142 in the cell. Consequently, low levels of miR-142 lead to the upregulation of TSLP expression. In the present study, we will further verify the regulation of LncRNA-AD1 on TSLP, and extensively investigate the role of LncRNA-AD1 in the onset of AD at the molecular level, cellular level and animal level. NC/Nga mice will be used as spontaneous AD model, and LncRNA-AD1 knockout mice will be used to establish induced AD model. Overall, we aim to elucidate the pathogenic pathway of “LncRNA-AD1 — miR-142 — TSLP — AD”, and provide additional insights towards the extensive understanding of AD.

特应性皮炎是一种病因复杂的炎症性皮肤病。胸腺基质淋巴生成素（TSLP）是一个启动特应性皮炎等Th2型过敏性炎症反应的重要分子，在特应性皮炎的皮损组织中表达明显升高，但其表达上调的原因并不明确。本课题组的前期研究发现，LncRNA-AD1是调控TSLP表达水平的重要因素之一。LncRNA-AD1是一种长链非编码RNA，在特应性皮炎的皮损组织中表达升高，并通过竞争性结合miR-142而调控TSLP的表达，其与TSLP的表达水平呈现明显的相关性。因此，本项目拟在前期研究基础上，进一步明确LncRNA-AD1对TSLP的调控作用，并通过NC/Nga小鼠和LncRNA-AD1基因敲除小鼠，在分子、细胞和整体动物水平探讨LncRNA-AD1参与特应性皮炎发病的具体作用机制。本项目旨在完善“LncRNA-AD1—miR-142—TSLP—特应性皮炎”这一致病途径，为特应性皮炎的机制研究提供新的线索。

本项目在前期研究的基础上，以NC/Nga小鼠和LncRNA-AD1基因敲除小鼠作为主要模型，并通过腺病毒在小鼠角质形成细胞中进行相关基因的过表达或敲减，从分子生物学、细胞和整体动物水平探讨LncRNA-AD1通过miR-142调控胸腺基质淋巴生成素（TSLP）的表达而参与特应性皮炎病理过程的具体作用机制。特应性皮炎是一种病因复杂的炎症性皮肤病。LncRNA-AD1是一种长链非编码RNA，在特应性皮炎的皮损组织中表达升高，并通过竞争性结合miR-142而调控TSLP的表达，并且验证了TSLP是miR-142的靶点之一。但是，LncRNA-AD1在特应性皮炎中的作用仍需进一步验证，其参与特应性皮炎病理过程的具体机制也尚未明确。因此，本项目为临床治疗特应性皮炎提供新的理论依据，并阐明了“LncRNA-AD1—miR-142—TSLP—特应性皮炎”这一致病途径。