PRECLINICAL STUDIES ON HUMAN FIBROIDS IN IMMUNODEFICIENT MICE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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。 对于该模型，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。最近的研究表明磷脂酰肌醇-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。 在IRB批准和知情同意后，从在OHSU医院接受子宫切除术的10名妇女收集纤维瘤组织，并皮下移植到卵巢切除的小鼠中。 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。

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.