Lgr5调控嗅上皮生长和促进损伤修复的分子机制研究

嗅上皮具有自我修复的能力，这主要由于嗅上皮中存在具有干细胞特性的基底细胞。球状基底细胞可以分化为支持细胞和嗅神经元。当嗅上皮受损时，水平状基底细胞被激活并介导嗅上皮修复。因此调控基底细胞分化为治疗神经元死亡导致的嗅觉障碍提供了新的方向。我们前期研究表明富含亮氨酸重复单位的G蛋白偶联受体5（Lgr5）在基底细胞中表达并在嗅上皮受损后被激活，参与嗅上皮修复。在本项目中，我们将通过调控Lgr5的表达揭示其在维持嗅上皮基底细胞的干细胞特性中的作用，并在Lgr5阳性细胞缺失模型中研究Lgr5阳性细胞在嗅上皮修复中的必要性及是否存在Lgr5阳性细胞的前体细胞。通过信号通路调控阐明Lgr5介导修复受损嗅上皮的分子机制并绘制Lgr5阳性干细胞增殖分化调控网络。综上所述，本研究将深入探索Lgr5在嗅上皮基底细胞增殖分化以及组织修复中的作用机制，为治疗由神经元死亡引起的嗅觉疾病提供新的思路和靶点。

Olfactory epithelium (OE) has the capacity to self-repair. This is due to the presence of basal cells that have the property of stem cells in the OE. Globose basal cells generate supporting cells, sensory neurons and other cellular subtypes in the OE. The quiescent horizontal basal cells (HBCs) are activated in lesioned OE, then participating in the OE repair. Thus, regulating basal cells to generate olfactory sensory neurons provides new clue to therapy against olfactory dysfunction. In this proposal, we will determine the role of Lgr5 in regulating the stem cell property of OE basal cells. Meanwhile, we will explain the necessity of Lgr5+ cells in the recovery of lesioned OE and identify the progenitors to Lgr5+ cells. Through modulating the signal pathway in transgenic mice, we will elucidate the molecular mechanism underlying OE recovery mediated by Lgr5+ cells and establish the signal transduction network showing the regulation of Lgr5+ stem cell proliferation and differentiation. Collectively, this project will probe into the role and underlying mechanisms of Lgr5 in proliferation and differentiation of OE basal cells as well as in OE recovery, providing new thoughts and targets in the treatment of olfactory dysfunction induced by sensory neuronal death.