PRECLINICAL STUDIES ON HUMAN FIBROIDS IN IMMUNODEFICIENT MICE

免疫缺陷小鼠人体肌瘤的临床前研究

• 批准号: 8357768
• 负责人: OV D SLAYDEN
• 金额: $ 5.82万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357768
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Age; Androgen Analogues; Androgen Antagonists; Androgen Receptor; Androgens; Androstenedione; Animal Model; Benign; CCI-779; Cell Proliferation; Cell Proliferation Regulation; Cells; Disease; Estradiol; Fibroid Tumor; Funding; Goals; Grant; Growth; High Prevalence; Human; Hysterectomy; Immunodeficient Mouse; Implant; Leiomyoma; Mediator of activation protein; Mus; Myometrial; National Center for Research Resources; Primates; Principal Investigator; Progesterone; Reporting; Research; Research Infrastructure; Resources; SCID Mice; Signal Pathway; Sirolimus; Source; Steroids; System; Testing; Transplantation; United States National Institutes of Health; Uterine Fibroids; Woman; Xenograft Model; cost; mouse model; myometrium; novel; preclinical study; reproductive; tumor

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 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％的生殖年龄妇女。 尽管生殖年龄妇女的肌瘤患病率很高，但肌瘤疾病的动物模型很少。为了填补这一空白，我们创建了一种人类异种移植模型，用于人类肌瘤的临床前研究。 从接受子宫切除术的妇女中收集肌瘤，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纤维疗法对这些小鼠中肌瘤和肌层移植物生长的影响。 磷脂酰肌醇-3激酶（PI3K）/AKT信号通路可能参与肌瘤细胞中细胞增殖的类固醇调节。 雷帕霉素的哺乳动物靶标是PI3K/AKT的下游介质。 我们测试了雷帕霉素和贝兹35（雷帕霉素类似物）对肌瘤植物生长的影响。 携带移植物的小鼠用植入物治疗雌二醇（E2），孕酮（P），E2 + P，E2 + P +雷帕霉素，或和E2 + P + BEZ235。 雷帕霉素在我们的小鼠模型中显着降低了肌瘤的生长。 BEZ235并没有减少移植物的大小，但确实减少了肌瘤细胞的增殖。 现在，我们还对几个雄激素受体调节剂进行了研究。 我们报告说，雄激素的合成雄激素和DHT可以减少该系统中人肌瘤移植物的生长。