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 子宫内膜增生是子宫内膜癌（EC）的前兆。复杂性非典型增生（CAH）是一种 一种常见的子宫内膜增生，如果不治疗，52%的病例会变成EC。 大多数CAH女性 可以治愈 子宫切除术， 切除子宫的手术 然而，对以下方面的需求日益增加： CAH和EC的生育保留治疗，特别是对于希望维持 生育CAH和EC的年轻女性中有20%至30%可能符合生育保留的条件 approach.开发保留生育力的治疗方法来治愈CAH和EC而不牺牲生育力仍然是一个挑战。 CAH和EC医学的基本目标。对孕酮（P4）抵抗机制的认识不足 是发展生育保留治疗的主要障碍。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CAH和EC的有效治疗方法。但 对P4治疗的反应率各不相同，新发或获得性P4耐药背后的分子机制是 不太了解。为了提高P4治疗作为保留生育力治疗的成功率， CAH和EC中P4耐药的潜在机制以及人类P4反应性的生物标志物 CAH和EC至关重要。丝裂原诱导基因6（mitogen-inducible gene 6，MAPK-6）是人类中关键的P4信号传导介质， 小鼠子宫。初步结果显示，P4-应答性（Sprr 2fcre/+Mig-6 f/f; Mig-6 Ep-KO）和P4-抗性 （Pgrcre/+Mig-6 f/f; Mig-6 KO）小鼠模型通过AKT和ERK的异常磷酸化发展CAH， 子宫内膜上皮细胞在P4反应小鼠中，P4控制CAH，恢复子宫容受性，并保留 生育在P4耐药小鼠中，P4不能控制CAH，不能恢复子宫容受性，也不能保护 生育这些数据表明，Mig-6缺失通过激活AKT信号转导导致P4抗性CAH的假设 在子宫内膜上皮细胞中的表达以及子宫内膜间质和上皮细胞中P4信号的失调。这 本项目将通过以下方式研究P4抗性的机制：1）剖析P4 -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）研究子宫内膜上皮细胞中基质MMP-6的功能， 3）测试P4 + AKT或mTOR抑制的组合疗法是否可以治疗P4抗性的 CAH和恢复子宫内膜功能，包括生育能力;和4）进行生物信息学分析研究， 将明确PGR的转录调控功能，寻找P4抗性的生物标志物。这项工作 将导致转化的结果，包括开发新的治疗方法， 治疗以及发现新的生物标志物，这对不孕症的精准医学很重要。