突变型组胺H4受体在特应性皮炎中的作用机制研究

Histamine H4 receptor (HH4R) plays an important role in allergic disorders and autoimmune diseases. HH4R is a G-protein-coupled receptor which functions through phospholipase C (PLC) and adenylate cyclase (AC) signal pathways. In our previous study, we identified three new mutations in HH4R which are significantly associated with the disease risk of atopic dermatitis (AD). Two consecutive mutations in the exon of HH4R affect the chemotaxis of mast cells. However, the molecular mechanisms of these mutations in the pathogenesis of AD remain unclear. In the present study, we will extensively elucidate the role of HH4R mutations in AD at molecular level, cell level and animal level. Human mast cell line (HMC-1) and dendritic cell line (DC2.4) will be used to examine whether HH4R mutations affect the biological functions of mast cells and dendritic cells through G-protein signal pathway. Moreover, Nc/Nga mice and mutated-HH4R knock-in mice will be used as spontaneous and induced AD models, respectively, to investigate the role of HH4R in the pathogenesis of AD. Overall, we aim to explore the possible connections for the line of HH4R mutations - G protein signaling - mast cell and dendritic cell function - pathogenesis of AD, and provide additional insights towards the clinical treatment of AD.

组胺H4受体在机体的过敏和炎症反应中具有重要作用，其在细胞内与G蛋白相互作用，主要通过腺苷酸环化酶系统及磷脂酶C系统发挥功能。在本课题组的前期研究中，发现了组胺H4受体的三个新的功能性突变位点，且与特应性皮炎的疾病风险具有显著相关性。其中，位于外显子区域的两个连续位点可以影响肥大细胞的趋化，但是，其在特应性皮炎病理过程中的分子生物学机制尚未明确。因此，本项目拟在前期研究基础上，应用人肥大细胞系HMC-1及人树突状细胞系DC2.4为主要的细胞模型、Nc/Ngc小鼠和突变型组胺H4受体基因敲入小鼠为自发性和诱发性特应性皮炎的动物模型，从分子生物学水平、细胞学水平和整体动物水平探讨突变型组胺H4受体在特应性皮炎中的作用及其机制。本项目旨在明确突变型组胺H4受体通过G蛋白信号传导通路影响肥大细胞及树突状细胞的生物学功能、进而参与特应性皮炎的病理过程，并为临床治疗特应性皮炎提供新的理论依据。

本项目应用人肥大细胞系HMC-1及人树突状细胞系DC2.4为主要的细胞模型、Nc/Ngc小鼠和突变型组胺H4受体基因敲入小鼠为自发性和诱发性特应性皮炎的动物模型，从分子生物学水平、细胞学水平和整体动物水平探讨了突变型组胺H4受体在特应性皮炎中的作用及其机制。本项目明确了突变型组胺H4受体影响G蛋白信号传导通路的生物学活性，进而影响肥大细胞及树突状细胞的生物学功能。通过自发性（Nc/Nga小鼠）及诱发性（基因敲入小鼠）特应性皮炎小鼠模型验证了突变型组胺H4受体参与特应性皮炎的病理过程。组胺H4受体在机体的过敏和炎症反应中具有重要作用，其在细胞内与G蛋白相互作用，主要通过腺苷酸环化酶系统及磷脂酶C系统发挥功能。在本课题组的前期研究中，发现了组胺H4受体的三个新的功能性突变位点，且与特应性皮炎的疾病风险具有显著相关性。其中，位于外显子区域的两个连续位点可以影响肥大细胞的趋化，但是，其在特应性皮炎病理过程中的分子生物学机制尚未明确。因此，本项目为临床治疗特应性皮炎提供了新的理论依据。