Unravelling mechanisms and novel therapeutic targets for progesterone-resistant endometrial hyperplasia

揭示黄体酮抵抗性子宫内膜增生的机制和新的治疗靶点

• 批准号: 10710998
• 负责人: Tae Hoon Kim
• 金额: $ 45.89万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710998
• 关键词: Age; Animal Model; Attenuated; Atypical hyperplasia; Bioinformatics; Biological Markers; Combined Modality Therapy; Complex; Data; Development; Eligibility Determination; Endometrial; Endometrial Carcinoma; Endometrial Hyperplasia; Endometrial Stromal Cell; Endometrium; Epithelial Cells; Epithelium; Excision; FRAP1 gene; Fertility; Fertility Rates; Future; Gene Expression; Genes; Genetic Transcription; Goals; Gynecologic; Human; Hysterectomy; Infertility; Knock-out; Left; Light; Mediating; Mediator; Medicine; Mitogens; Modeling; Molecular; Mus; Operative Surgical Procedures; Outcome; Patients; Phosphorylation; Progesterone; Progesterone Receptors; Proliferating; Receptor Signaling; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Uterus; Woman; Work; aged; cancer therapy; comparison control; conditional knockout; fertility preservation; hormone therapy; inhibitor; insight; mTOR inhibition; mouse model; myometrium; new therapeutic target; novel; novel therapeutic intervention; patient response; precision medicine; preservation; prevent; receptor expression; reproductive; response; success; targeted treatment; tool; uterine receptivity; young woman

Project Summary Endometrial hyperplasia is a precursor to endometrial cancer (EC). Complex atypical hyperplasia (CAH) is the common type of endometrial hyperplasia that becomes EC in 52% of cases if not treated. Most women with CAH can be cured by hysterectomy, the surgical removal of the uterus. However, there is an increasing demand for fertility-sparing treatments for CAH and EC, especially for reproductive-aged women who wish to maintain fertility. Twenty to thirty percent of the young women with CAH and EC might be eligible for a fertility sparing approach. Developing fertility-sparing treatments to cure CAH and EC without sacrificing fertility remains an essential goal in CAH and EC medicine. Poor understanding of the mechanism of progesterone (P4) resistance in CAH and EC is a major barrier to developing fertility-sparing treatment. P4 is widely used to treat various gynecological conditions due to its clear antiproliferative effects on E2-mediated endometrial proliferation. P4, the gold standard of nonsurgical treatment, is often an effective CAH and EC treatment. However, the response rates to P4 therapy vary and molecular mechanisms behind de novo or acquired P4 resistance are poorly understood. To increase success rates of P4 therapy as a fertility-sparing treatment, revealing the mechanisms underlying P4 resistance in CAH and EC and finding biomarkers for P4 responsiveness in human CAH and EC are critical. The mitogen-inducible gene 6 (MIG-6) is a key P4 signaling mediator in the human and mouse uterus. Preliminary results show that P4-responsive (Sprr2fcre/+Mig-6f/f; Mig-6Ep-KO) and P4-resistant (Pgrcre/+Mig-6f/f; Mig-6KO) mouse models develop CAH via aberrant phosphorylation of AKT and ERK in endometrial epithelial cells. In P4-responsive mice, P4 controls CAH, restores uterine receptivity, and preserves fertility. In P4-resistant mice, P4 fails to control CAH, fails to restore uterine receptivity, and fails to preserve fertility. These data suggest the hypothesis that Mig-6 loss causes P4-resistant CAH by activating AKT signaling in endometrial epithelial cells and by dysregulating P4 signaling in endometrial stromal and epithelial cells. This project will investigate the mechanism of P4-resistance by: 1) dissecting the role of MIG-6 in the interaction between AKT and PGR signaling in endometrial epithelial cells; 2) studying the function of stromal MIG-6 in response to P4; 3) testing whether combination therapy of P4 + AKT or mTOR inhibition can treat P4-resistant CAH and restore endometrial function, including fertility; and 4) conducting bioinformatic analysis study that will identify the transcriptional regulatory function of PGR and find the biomarkers in P4 resistance. This work will lead to translational outcomes including the development of new therapeutic approaches for fertility-sparing treatment as well as discovery of new biomarkers, which are important for Precision Medicine in infertility.

项目摘要 子宫内膜增生症是子宫内膜癌(EC)的先兆。复杂性不典型增生(CAH)是 常见类型的子宫内膜增生症，如果不治疗，52%的病例会变成EC。 大多数女性CAH患者 可以通过以下方法治愈 子宫切除术， 子宫切除手术切除子宫的手术 然而，对……的需求在增加 保留生育能力的CAH和EC治疗，特别是对于希望维持生育年龄的妇女 生育能力。患有CAH和EC的年轻女性中有20%到30%可能符合保留生育的条件 接近。开发在不牺牲生育能力的情况下治愈CAH和EC的节省生育能力的治疗方法仍然是 CAH和EC医学的基本目标。对孕酮(P4)耐药机制认识不足 CAH和EC是发展保留生育治疗的主要障碍。P4被广泛用于治疗各种疾病 妇科疾病，因为它对E2介导的子宫内膜增殖有明显的抗增殖作用。 P4是非手术治疗的金标准，通常是治疗CAH和EC的有效方法。然而， 对P4治疗的应答率不同，新发或获得性P4耐药背后的分子机制是 人们对此知之甚少。为了提高P4疗法作为一种节省生育能力的治疗的成功率，揭示了 CAH和EC中P4耐药的机制及P4应答的生物标志物的寻找 CAH和EC是关键。丝裂原诱导基因6(MIG-6)是人类和 小鼠子宫。初步结果表明，P4敏感(Sprr2fcre/+Mig-6f/f；Mig-6Ep-KO)和P4抗性 (Pgrcre/+Mig-6f/f；Mig-6KO)小鼠模型通过AKT和ERK的异常磷酸化发生CAH 子宫内膜上皮细胞。在P4反应的小鼠中，P4控制CAH，恢复子宫容受性，并保存 生育能力。在P4耐药小鼠中，P4不能控制CAH，不能恢复子宫容受性，也不能保存 生育能力。这些数据表明，Mig-6缺失通过激活AKT信号导致P4耐药CAH的假设 在子宫内膜上皮细胞中，通过对子宫内膜间质和上皮细胞中P4信号的失调而发挥作用。这 该项目将通过以下方式研究P4抗性的机制：1)剖析MIG-6在相互作用中的作用 AKT和PGR信号在子宫内膜上皮细胞中的作用；2)研究基质MIG-6在子宫内膜上皮细胞中的作用 对P4的反应；3)检测P4+AKT或mTOR抑制联合治疗是否能治疗P4耐药 CAH和恢复子宫内膜功能，包括生育；以及4)进行生物信息学分析研究， 将鉴定PGR的转录调控功能，寻找P4耐药的生物标志物。这部作品 将导致转化的结果，包括开发新的节育治疗方法 治疗以及新生物标志物的发现，这对精准医学治疗不孕不育具有重要意义。