Uterine Leiomyoma Research Center Program

子宫肌瘤研究中心计划

• 批准号: 8308004
• 负责人: Serdar E. Bulun
• 金额: $ 112.72万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308004
• 关键词: Affect; Anemia; Anti-Progestin; Apoptosis; Benign; Cell Culture Techniques; Cell Survival; Cells; Collagen Type I; Development; Disease; Environment; Exhibits; Extracellular Matrix; Fibroid Tumor; Future; Genes; Goals; Growth; Growth and Development function; Gynecologic; Hormonal; Hysterectomy; Instruction; Lead; Leiomyoma; Molecular; PI3K/AKT; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pregnancy loss; Progesterone; Progesterone Receptors; Progestins; Proto-Oncogene Proteins c-akt; RU-486; Recurrence; Research; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Testing; Tissue Procurements; Transforming Growth Factor beta; Type I Epithelial Receptor Cell; Uterine Fibroids; Uterine hemorrhage; Woman; cell growth; design; inhibitor/antagonist; multidisciplinary; novel therapeutics; programs; response; transcription factor; translational study; tumor; tumor growth

Uterine leiomyomata (fibroids) represent the most prevalent benign gynecologic disorder in the US. The cellular and molecular mechanisms regulating the development and growth of leiomyoma are not well understood. Our multidisciplinary team has designed 3 well-integrated projects focusing on Interactions between biologically critical hormonal pathways in uterine leiomyoma involving the transcription factors progesterone receptor (PR) and FOXO, the signaling pathway PI3K/AKT and the pro-fibrotic factor TGF-beta. Project I (Bulun) will be pursued to understand the mechanisms as to how antl-progestins such as RU486 reduce tumor size. We hypothesize that progesterone regulates a number of critical genes, that favors increased proliferation and decreased apoptosis of leiomyoma smooth muscle cells, whereas anti-progestins reverse this effect by enhancing apoptosis and decreasing proliferation. Project II (Kim/Chakravarti) will determine the role of the PI3K/AKT/F0X0 signaling pathway regulating leiomyoma cell growth and survival in response to progesterone. We hypothesize that progesterone Induces proliferation of leiomyoma cells through activation of the PI3K/AKT/F0X0 signaling pathway and that Inhibitors of the AKT pathway should override the proliferative effects of progesterone and promote apoptosis. Project III (Nowak) will define the mechanisms as to how antifibrotic drugs regulate leiomyoma growth. We hypothesize that the Increased proliferation exhibited by leiomyoma smooth muscle cells Is due to a major shift in the extracellular matrix environment caused by increased synthesis of new, monomeric collagen type I by these cells. We will determine whether antifibrotic drugs may be an effective new treatment for leiomyomas. These projects are supported by an Administrative Core (Bulun) and Tissue Procurement and Cell Culture Core (Kurita). Overall, as part of our long range goal, all projects investigate local hormonal signaling regulating apoptosis and proliferation as biologic endpoints and test existing and upcoming pharmaceutical compounds that target these pathways in uterine leiomyomata.

子宫平滑肌瘤（肌瘤）是美国最常见的良性妇科疾病。这 调节平滑肌瘤发生和生长的细胞和分子机制尚不完善 明白了。我们的多学科团队设计了 3 个专注于交互的综合项目 子宫肌瘤中涉及转录因子的生物学关键激素途径之间的关系 黄体酮受体 (PR) 和 FOXO、信号通路 PI3K/AKT 和促纤维化因子 TGF-β。 项目 I（Bulun）将致力于了解抗孕激素（例如 RU486）如何发挥作用的机制 减小肿瘤大小。我们假设黄体酮调节许多关键基因，这有利于 增加平滑肌瘤平滑肌细胞的增殖并减少细胞凋亡，而抗孕激素 通过增强细胞凋亡和减少增殖来逆转这种效应。项目 II（Kim/Chakravarti）将 确定 PI3K/AKT/F0X0 信号通路调节平滑肌瘤细胞生长和存活的作用 对黄体酮的反应。我们假设黄体酮诱导平滑肌瘤细胞增殖 通过激活 PI3K/AKT/F0X0 信号通路，AKT 通路抑制剂应该 克服黄体酮的增殖作用并促进细胞凋亡。项目 III (Nowak) 将定义 抗纤维化药物如何调节平滑肌瘤生长的机制。我们假设增加 平滑肌瘤平滑肌细胞表现出的增殖是由于细胞外基质的重大转变 由于这些细胞合成新的单体 I 型胶原蛋白的增加而引起的环境变化。我们将 确定抗纤维化药物是否可能是平滑肌瘤的有效新疗法。这些项目是 由行政核心 (Bulun) 和组织采购和细胞培养核心 (Kurita) 提供支持。 总的来说，作为我们长期目标的一部分，所有项目都研究调节细胞凋亡的局部激素信号 和增殖作为生物终点，并测试现有和即将推出的靶向药物化合物 子宫平滑肌瘤中的这些途径。