PRECLINICAL STUDIES ON HUMAN FIBROIDS IN IMMUNODEFICIENT MICE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 子宫肌瘤是子宫肌肉或子宫肌层的良性肿瘤，影响25%-40%的育龄妇女。尽管育龄妇女中子宫肌瘤的发病率很高，但几乎没有肌瘤病的动物模型。为了填补这一空白，我们创建了一个人类异种移植模型，用于人类肌瘤的临床前研究。在这个模型中，从接受子宫切除术的妇女身上收集肌瘤，并将其移植到免疫缺陷的SCID小鼠中进行研究。我们的目标是测试包括雄激素和雄激素拮抗剂在内的新型抗肌瘤疗法对这些小鼠肌瘤和肌层移植物生长的影响。最近的研究表明，磷脂酰肌醇-3激酶(PI3K)/Akt信号通路可能参与了类固醇对肌瘤细胞增殖的调节。哺乳动物对雷帕霉素的靶点是PI3K/Akt的下游介导物。我们检测了雷帕霉素和BEZ35(雷帕霉素类似物)对肌瘤移植物生长的影响。子宫肌瘤组织取自10名在OHSU医院接受子宫切除术的妇女，经IRB批准和知情同意后，移植到去卵巢小鼠的皮下。携带移植物的小鼠接受释放雌二醇(E2)、孕酮(P)、E2+P、E2+P+雷帕霉素或和E2+P+BEZ235的植入物治疗。在我们的小鼠模型中，雷帕霉素显著减少了肌瘤的生长。BEZ235不能减少移植物的大小，但能减少肌瘤细胞的增殖。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Uterine fibroids (leiomyomata) are benign tumors of the uterine muscle or myometrium that affect 25-40% of women of reproductive age. Despite the high prevalence of fibroids in reproductive age women, there are few animal models for fibroid disease. To fill this gap we created a human xenograft model for preclinical studies of human fibroids. For this model, fibroids are collected from women undergoing hysterectomy and transplanted into immunodeficient SCID mice for study. Our goal was to test the effects of novel anti-fibroid therapies including androgens and androgen antagonists on growth of fibroid and myometrial grafts in these mice. Recent studies indicate that the hosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway may participate in steroid regulation of cell proliferation in fibroid cells. The mammalian target for rapamycin is a downstream mediator of PI3K/Akt. We tested the effect of rapamycin, and BEZ35 (a rapamycin analog) on fibroid graft growth. Fibroid tissues were collected from 10 women undergoing hysterectomy at the OHSU Hospital after IRB approval and informed consent and subcutaneous grafted into ovariectomized mice. The mice bearing the grafts were treated with implants releasing either estradiol (E2), progesterone (P), E2 + P, E2 + P + Rapamycin, or and E2 + P + BEZ235. Rapamycin significantly reduce fibroid growth in our mouse model. BEZ235 did not reduce graft size, but did reduced fibroid cell proliferation.