PTCH1突变激活Hedgehog通路诱导CRSwNP产生差异化病理类型的分子机制研究

慢性鼻窦炎伴息肉（CRSwNP）是一种长期慢性炎症性疾病，发病机制不清。CRSwNP与黏膜慢性炎症和组织重塑有关，不同组织重塑形式可导致差异化病理分型，影响治疗和预后。研究表明PTCH1基因参与炎症过程，其突变是激活Hedgehog通路的重要机制。我们前期研究发现，水肿型嗜酸性CRSwNP中PTCH1高频胚系突变，蛋白表达于上皮及炎细胞。为此我们提出本项目科学假说：CRSwNP发生发展中，PTCH1突变激活Hedgehog通路调控上皮细胞增殖增强，凋亡减弱及细胞因子分泌，同时启动上皮细胞上皮间质转化，参与组织重塑，导致不同病理分型息肉形成。为验证此假说，本课题拟利用体内外试验，明确PTCH1突变与CRSwNP临床病理亚型特征相关性及分子分型的可行性和其在CRSwNP发展中的作用，揭示PTCH1在形成不同病理亚型CRSwNP中的机制，为分子病理分型及预后提供理论依据，为临床治疗提供可能靶点。

Chronic sinusitis with polyps (CRSwNP) is a long-term chronic inflammatory disease with unclear pathogenesis. CRSwNP is related to chronic mucosal inflammation and tissue remodeling, and different forms of tissue remodeling can lead to differential pathological subtype, affecting treatment and prognosis. Studies have shown that PTCH1 is involved in inflammatory processes, and its mutation is an important mechanism for activating the Hedgehog pathway. Our previous study found that PTCH1 had a high frequency germline mutation in edematous eosinophilic CRSwNP, and the protein was expressed in epithelial and inflammatory cells. To this end, we propose the scientific hypothesis of this project: during the development of CRSwNP, PTCH1 mutation activates Hedgehog pathway to regulate the proliferation and apoptosis of epithelial cells and cytokine secretion, and at the same time initiates the process of epithelial cell epithelial mesenchymal transformation, participates in tissue remodeling, and finally leads to the formation of polyps of differentiated pathological subtype. To test this hypothesis, this topic is proposed to use experiments in vitro and in vivo, clear the correlation with clinical pathological subtype of CRSwNP and PTCH1 mutations, clarify the feasibility which it acted as the molecular markers of molecular classification and the role of development in CRSwNP. We try to reveal the mechanism of PTCH1 mutation in forming different pathological subtype of CRSwNP, provide theoretical basis for molecular pathology classification and prognosis, and provide possible targets for clinical treatment.