PRECLINICAL STUDIES ON HUMAN FIBROIDS IN IMMUNODEFICIENT MICE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心赠款提供。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 子宫肌瘤（平滑肌瘤）是子宫肌肉或肌层的良性肿瘤，影响25-40%的育龄妇女。 尽管在育龄妇女中纤维瘤的患病率很高，但纤维瘤疾病的动物模型很少。为了填补这一空白，我们建立了一个人类异种移植模型，用于人类肌瘤的临床前研究。 从经历子宫切除术的妇女收集纤维瘤并移植到免疫缺陷的SCID小鼠中用于研究。 我们的目标是测试新的抗纤维瘤疗法，包括雄激素和雄激素拮抗剂对这些小鼠的纤维瘤和子宫肌层移植物生长的影响。 磷脂酰肌醇-3激酶（PI 3 K）/Akt信号通路可能参与类固醇激素对纤维瘤细胞增殖的调控。 雷帕霉素的哺乳动物靶标是PI 3 K/Akt的下游介质。 我们测试了雷帕霉素和BEZ 35（雷帕霉素类似物）对纤维瘤移植物生长的影响。 携带移植物的小鼠用释放雌二醇（E2）、孕酮（P）、E2 + P、E2 + P +雷帕霉素或E2 + P+雷帕霉素的植入物处理。 和E2 + P + BEZ 235。 在我们的小鼠模型中，雷帕霉素显著减少纤维瘤生长。 BEZ 235没有减少移植物的大小，但减少了纤维瘤细胞的增殖。 我们现在还进行了几项雄激素受体调节剂的研究。 我们报告雄烯二酮，EF-MENT一种合成雄激素，和DHT可以减少人类子宫肌瘤移植物在这个系统中的生长。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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. 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. The phosphatidylinositol-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. 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 reduce fibroid cell proliferation. We have now also conducted studies with several androgen receptor modulators. We report that Androstenedione, eF-MENT a synthetic androgen, and DHT can reduce growth of human fibroid grafts in this system.