口腔黏膜化学感官细胞维持口腔微生态平衡的作用与分子机制研究

The extragustatory cells that express taste receptors are named as chemosensory cells. Recent studies have shown that extragustatory chemosensory cells can sense microbial signals and modulate microbial and host homeostasis. However, the tissue distribution of oral chemosensory cells and their role in regulating oral microbial ecology are yet to be investigated. Our previous study has shown the existence of chemosensory cells in mouse oral cavity. In addition, deletion of Gustducin, the key component of the downstream chemoreceptorial cascade, led to a compromised generation of antimicrobial peptide and increased severity of periodontitis, indicating a critical role of oral chemosensory cells in maintaining oral homeostasis. Hence, we hypothesize that oral chemosensory cells can respond to microbial signals and regulate oral microbial ecology, and thus play a critical role in the occurrence and progression of oral infectious diseases. To validate this hypothesis, this proposal will further identify the subtypes of taste receptors that expressed by chemosensory cells and locate their tissue distribution in the oral mucosa of mice. The mechanisms by which chemosensory cells mediate oral microbes and host interactions will be further investigated with transgenic mouse models. We will further employ a periodontitis mouse model to investigate whether the oral microbial dysbiosis induced by the knock-out of downstream cascade key components could increase the susceptibility/severity of periodontitis. Clinical volunteers will also be recruited and their taste receptor polymorphisms will be genotyped and further correlated with oral microbiome structure and periodontal health. Results obtained from this proposed study will not only provide molecular mechanisms by which chemosensory cells and the downstream chemoreceptorial cascade regulate oral homeostasis, but may also contribute to the susceptibility screening and personalized treatment of oral infectious diseases.

近期研究发现，除味蕾外，多种组织细胞都表达了味觉受体，这组细胞被称为化学感官细胞（CSC），具有识别微生物信号，调控微生物与宿主稳态的作用（Nature, 2016），但口腔内是否存在此类细胞及其对口腔微生态的影响尚未见报道。申请人前期发现，小鼠口腔黏膜存在类似细胞，敲除这群细胞的化学感官信号转导关键元件导致局部炎症加重。因此假定，存在于口腔的CSC可识别口腔微生物信号，调控微生态平衡，参与口腔感染性疾病的发生发展。为验证此假说，本项目拟首先以小鼠为对象，通过组织学研究，进一步确定CSC在口腔中的分布及其味觉受体亚型；借助转基因小鼠模型，研究CSC与微生物组交互作用的分子机制；并在牙周炎小鼠模型上，验证CSC功能缺失的致病性；最后，通过牙周炎人群味觉基因多态性与微生物组、炎症程度的关联分析，确认CSC调控口腔微生态平衡，参与口腔感染性疾病发生发展的作用，指导疾病个体化医疗及易感人群筛查。

除味蕾外，机体多种组织细胞均可表达苦味受体，被称为化学感官细胞，具有识别微生物信号，调控微生物与宿主稳态的作用。本项目基于前期研究，提出研究假设：牙龈存在化学感官细胞，可识别口腔微生物信号或苦味刺激，调控微生态平衡，参与牙周炎的发生发展。为验证该假设，本项目通过建立味导素缺失小鼠牙周炎模型，探究了牙周化学感官细胞在牙周免疫反应及牙周微生态平衡中的作用与机制；通过构建人牙龈成纤维细胞体外炎症模型，探究了牙龈成纤维细胞苦味受体及味觉信号传导通路参与牙周炎症反应的分子机制；通过建立牙周炎临床队列，探究了TAS2R38基因多态性与牙周炎易感性及基础治疗预后的相关性。项目研究发现牙龈存在表达苦味受体的化学感官细胞，通过苦味信号传导通路影响口腔微生物多样性及菌群组成，并进一步影响牙槽骨生理性吸收速度及牙周炎严重程度，人群苦味受体TAS2R38基因多态性与牙周炎的发生与治疗预后有关。研究结果有望为口腔黏膜化学感官细胞在维持口腔微生态平衡中作用与分子机制提供参考，为牙周炎的个体化医疗及易感人群重点防控提供理论依据。