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.

项目概要 子宫内膜增生是子宫内膜癌（EC）的前兆。复杂性非典型增生（CAH）是 子宫内膜增生的常见类型，如果不治疗，52% 的病例会变成 EC。 大多数患有 CAH 的女性 可以通过以下方法治愈 子宫切除术， 手术切除子宫。 然而，人们对 CAH 和 EC 的保留生育治疗，特别是对于希望维持生育能力的育龄妇女 生育能力。百分之二十到三十的患有 CAH 和 EC 的年轻女性可能有资格获得生育保留 方法。开发保留生育能力的治疗方法以在不牺牲生育能力的情况下治愈 CAH 和 EC 仍然是一个难题 CAH 和 EC 医学的基本目标。对黄体酮（P4）抵抗机制了解甚少 CAH 和 EC 的发病率是开发保留生育治疗的主要障碍。 P4广泛用于治疗各种 由于其对 E2 介导的子宫内膜增殖具有明显的抗增殖作用，因此可用于妇科疾病。 P4 是非手术治疗的金标准，通常是有效的 CAH 和 EC 治疗方法。然而， P4 治疗的反应率各不相同，并且新发或获得性 P4 耐药性背后的分子机制是 不太了解。为了提高 P4 疗法作为保留生育治疗的成功率，揭示了 CAH 和 EC 中 P4 抗性的潜在机制，并寻找人类 P4 反应性的生物标志物 CAH 和 EC 至关重要。有丝分裂原诱导基因 6 (MIG-6) 是人类和细胞中关键的 P4 信号传导介质。 小鼠子宫。初步结果表明，P4 响应（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 的异常磷酸化产生 CAH 子宫内膜上皮细胞。在 P4 反应性小鼠中，P4 控制 CAH、恢复子宫容受性并保留 生育能力。在 P4 抗性小鼠中，P4 无法控制 CAH，无法恢复子宫容受性，并且无法保留 生育能力。这些数据表明 Mig-6 缺失通过激活 AKT 信号传导导致 P4 抵抗性 CAH 子宫内膜上皮细胞中的 P4 信号传导失调以及子宫内膜基质细胞和上皮细胞中的 P4 信号传导失调。这 该项目将通过以下方式研究 P4 抗性机制：1）剖析 MIG-6 在相互作用中的作用 子宫内膜上皮细胞中 AKT 和 PGR 信号传导之间的关系； 2)研究基质MIG-6在 对P4的回应； 3) 测试P4 + AKT或mTOR抑制的联合治疗是否可以治疗P4耐药 CAH 并恢复子宫内膜功能，包括生育能力； 4) 进行生物信息分析研究 将鉴定PGR的转录调控功能并找到P4抗性的生物标志物。这部作品 将带来转化成果，包括开发保留生育能力的新治疗方法 治疗以及新生物标志物的发现，这对于不孕不育症的精准医学非常重要。