TSC2突变导致子宫腺肌病的分子机制研究

子宫腺肌病（AM）是常见的难治性妇科疾病，其病因不明。本课题组前期研究首次发现约1/4的AM病灶中存在TSC2突变，但TSC2突变驱动AM发生的机制不清楚。本课题组体外实验进一步证实TSC2突变体易于发生泛素化途径介导的蛋白质降解，并通过mTOR信号通路抑制细胞自噬，进而促进细胞的增殖、侵袭和上皮间质转化（EMT）。因此，我们提出TSC2突变通过改变子宫内膜上皮细胞的生物学行为从而导致AM发生和发展的科学假说。本项目将在临床样本、细胞系和动物模型三个层面，研究TSC2突变致TSC2蛋白功能改变的原因；探讨TSC2突变对人子宫内膜上皮细胞功能的影响；从分子水平探寻TSC2下游关键靶基因和信号通路的改变；并构建TSC2突变型转基因小鼠模型进行在体实验，全面揭示TSC2突变导致AM发生的分子机制。本研究结果将为探索AM遗传学病因提供理论基础，为后续AM临床治疗和新药研发提供潜在靶点。

Adenomyosis (AM) is a common refractory gynecological disease, and its pathogenesis is unknown. In our previous research, TSC2 mutations were found in about 1/4 of AM lesions for the first time, but the mechanism by which TSC2 mutations drive AM is unclear. The in vitro experiments have further confirmed that TSC2 mutants are prone to protein degradation mediated by the ubiquitination pathway and inhibit cell autophagy through the mTOR signaling pathway, thereby promoting cell proliferation, invasion and epithelial mesenchymal transformation (EMT). Therefore, we propose a scientific hypothesis that TSC2 mutations cause the occurrence and development of AM by changing the biological behavior of endometrial epithelial cells. This project will study the causes of changes in TSC2 protein function caused by TSC2 mutations at three levels of clinical samples, cell lines and animal models; explore the effect of TSC2 mutations on human endometrial epithelial cell function; explore key target genes downstream of TSC2 and changes in signaling pathways; and constructing TSC2 mutant transgenic mouse models for in vivo experiments to fully reveal the molecular mechanism of TSC2 mutations leading to AM. The results of this study will provide a theoretical basis for exploring the genetic etiology of AM, and provide potential targets for the subsequent clinical treatment of AM and the development of new drugs.