Uterine Leiomyoma Research Center Program

子宫肌瘤(肌瘤)是美国最常见的良性妇科疾病。这个 调控子宫肌瘤发生和生长的细胞和分子机制尚不清楚 明白了。我们的多学科团队设计了3个专注于互动的综合项目 子宫肌瘤中涉及转录因子的生物学关键激素途径之间 孕激素受体(PR)和FOXO，信号通路PI3K/AKT和促纤维化因子TGF-β。 将继续执行项目I(Bulun)，以了解抗孕激素(如RU486)如何 缩小肿瘤大小。我们假设黄体酮调节一些关键基因，这有利于 抗孕激素促进子宫肌瘤平滑肌细胞增殖和减少细胞凋亡 通过促进细胞凋亡和抑制细胞增殖来逆转这一效应。项目二(Kim/Chakravarti)将 确定PI3K/AKT/F0X0信号通路在调控子宫肌瘤细胞生长和存活中的作用 对黄体酮的反应。我们假设黄体酮诱导子宫肌瘤细胞的增殖 通过激活PI3K/AKT/F0X0信号通路，AKT通路的抑制剂应该 抑制黄体酮的增殖作用，促进细胞凋亡。项目III(NOWAK)将定义 抗纤维化药物如何调节肌瘤生长的机制。我们假设增加的 肌瘤平滑肌细胞的增殖是由于细胞外基质发生了重大变化。 这些细胞增加合成新的单体I型胶原所造成的环境。我们会 确定抗纤维化药物是否可能是治疗肌瘤的有效新疗法。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。 总体而言，作为我们长期目标的一部分，所有项目都研究局部激素信号调节细胞凋亡。 和增殖作为生物终点，并测试现有和即将到来的药物化合物的目标 子宫肌瘤中的这些通路。

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.