Wnt/β-catenin信号通路在MEN1突变的胰岛素瘤发生中的作用机制及靶向治疗研究

Insulinoma is the most common functional pancreatic neuroendocrine tumor type. It is reported that inactivating MEN1 mutations are the proximal events, which are responsible for 44.1% of genetic defects, in sporadic and inherited pancreatic neuroendocrine tumors. Mining the molecular biological basis of tumorigenesis to search for effective therapeutic targets is the great challenge to reduce the incidence and mortality of MEN1-mutant insulinomas. Using the existing pancreatic β cell conditional menin and β-catenin knockout mouse model and the insulinoma tissue bank, we hope to systematically study the mechanisms of menin regulating Wnt/β-catenin signaling pathway on the basis of preliminary work. We would assess the functional role of Wnt / β-catenin signaling pathway in MEN1- deficient insulinomas, to explore the application of relevant results in clinical diagnosis, evaluation and treatment of insulinomas. In vivo intervention with small molecule drugs targeting Wnt/β-catenin signaling pathway to MEN1-deficient insulinomas would help us to explore the target of individualized drug therapy and provide the prospects of specific and effective therapeutic treatment.

胰岛素瘤是最常见的胰腺内分泌肿瘤类型。手术切除是治疗胰腺内分泌肿瘤的主要方法。研究表明MEN1基因突变是胰腺内分泌肿瘤中频率最高的突变。挖掘MEN1突变胰岛素瘤的分子生物学发病基础以寻找有效药物治疗靶点将成为降低胰腺内分泌肿瘤发病率和病死率的巨大挑战。本研究希望利用已有的胰岛β细胞条件性敲除Men1及β-catenin的小鼠模型和胰岛素瘤标本库，系统研究menin对Wnt / β-catenin信号通路的调控机制，以及Wnt / β-catenin信号通路在menin缺失的胰岛素瘤中的功能，揭示其调控机制对胰岛素瘤发生的影响，探索相关结果在临床诊断、评估和胰岛素瘤治疗策略中应用的途径。并利用靶向Wnt / β-catenin信号通路的小分子药物干预Men1缺失的胰岛素瘤，探讨胰岛素瘤的个体化分子靶向药物治疗的靶点，为MEN1突变型肿瘤提供特异及有效治疗前景。

本项目利用已有的胰岛β细胞条件性敲除menin及β-catenin的小鼠模型和胰岛素瘤组织标本库，系统研究了menin对Wnt / β-catenin信号通路的调控机制，以及Wnt / β-catenin信号通路在menin缺失的胰岛素瘤发生中的功能，深入阐述Wnt/β-catenin信号通路在胰岛生理性增殖和Men1缺失的胰岛素瘤发生中发挥的重要作用和分子机制。揭示了调控机制对胰岛素瘤发生的影响，探索相关结果在临床诊断、评估和胰岛素瘤治疗策略中应用的途径。利用Men1缺失的胰岛素瘤模型和临床胰岛素瘤资源，探索和筛选靶向Wnt/β-catenin信号通路的小分子药物在治疗胰腺内分泌肿瘤中的应用价值。本项目研究成果将为MEN1缺失的胰岛素瘤的发生机制和胰腺内分泌肿瘤的分子分型提供新的理论依据，为胰腺内分泌肿瘤的分子诊断，评估和个体化靶向治疗策略提供新的应用途径。