TISSUE INTERACTIONS AND HORMONAL RESPONSES IN THE UTERUS

描述：(改编自申请者的摘要)知道组织如何 相互作用影响生理学对于理解糖尿病的病理机制很重要 荷尔蒙调节器官。在子宫中，组织间的相互作用调节类固醇 荷尔蒙效应，在早孕事件中起着关键作用。虽然 雌激素在间质-上皮方向调节细胞信号转导 子宫，一种旁分泌因子，介导这一作用尚未确定。另外， 荷尔蒙对相互方向的途径的调节尚未得到 学习。在人类和啮齿动物中，雌激素对黄体酮的刺激作用 支配子宫会导致子宫内膜间质的增殖。建议 研究将检验这一假设：1)孕酮启动雌激素 子宫间质细胞增殖的诱导是间接发生的 通过激活孕激素受体(PR)和雌激素受体-α (ERα)在上覆上皮中。2)胰岛素样生长因子-I是一种旁分泌介质。 子宫中的类固醇作用。这一假设将通过组织进行检验。 在异种移植中生长的重组。子宫上皮与间充质 (MES)将来源于新生野生型小鼠，ERα基因敲除(ERα KO)小鼠、PR基因敲除(PRKO)小鼠或IGF-I基因敲除小鼠。这些淘汰赛 之所以选择模型是因为：ERαKO小鼠子宫没有生长反应 对雌二醇的刺激，表明它缺乏任何促进生长的作用 PRKO小鼠子宫对孕酮/雌激素无间质反应 治疗或去雄刺激；在IGF-I基因敲除小鼠子宫中 雌激素刺激的细胞滞留在G2期。具体目标是：1. 确定类固醇受体介导的事件的组织特异性 调节细胞增殖。2.确定组织特异性的作用 胰岛素样生长因子-I在类固醇诱导的血管内皮细胞增殖中的表达 子宫。对于每种类型的基因敲除动物，组织将被分离并 重组为所有4种可能的组合：EPI+/MES+、EPI-/MES-、EPI+/MES-、 EPI-/MES+(+，靶基因状态)。组织重组体将在无菌环境中生长 老鼠。激素治疗的效果将用氚胸苷进行测试 以融合指数或有丝分裂指数为终点。如果假设1被证明是正确的， 这将是荷尔蒙调节的一个新的演示，通过一个 上皮与间质的相互作用，从而产生了激素的新概念 在类固醇反应器官中的作用。如果IGF-I被证明对组织至关重要 相互作用它将是第一个确定的旁分泌因子 被认为是子宫中类固醇作用的中介物。

DESCRIPTION: (Adapted from the applicant's abstract) Knowing how tissue interactions affect physiology is important for understanding pathologies of hormonally regulated organs. In the uterus, tissue interactions mediate steroid hormone effects, playing key roles in events of early pregnancy. Although estrogen regulates cell signaling in a stroma-to-epithelium direction in the uterus, a paracrine factor mediating this effect has not been identified. Also, hormonal regulation of a pathway in the reciprocal direction has not been studied. In both human and rodent, estrogen stimulation of a progesterone dominated uterus causes proliferation of the endometrial stroma. Proposed studies will test the hypothesis: 1) Progesterone priming for and estrogen induction of cellular proliferation in the uterine stroma occurs indirectly through activation of progesterone receptor (PR) and estrogen receptor-alpha (ER alpha) in the overlying epithelium. 2) IGF-I is a paracrine mediator of steroid action in the uterus. The hypothesis will be tested using tissue recombinations grown in xenograft. Uterine epithelium (epi) and mesenchyme (mes) will be derived from neonatal wild-type mice, ER alpha knockout (ER alpha KO) mice, PR knockout (PRKO) mice, or IGF-I knockout mice. These knockout models were chosen because: ER alpha KO mouse uterus shows no growth response to estradiol stimulation, indicating that it is devoid of any growth-promoting ER; PRKO mouse uterus exhibits no stromal response to progesterone/estrogen treatment or to a decidualizing stimulus; in the IGF-I knockout mouse uterus estrogen stimulated cells are arrested in G2. The specific aims are: 1. Determine the tissue specificity of the steroid receptor-mediated events regulating cell proliferation. 2. Determine the role of tissue specific expression of IGF-I in mediation of steroid induced proliferation in the uterus. For each type of knockout animal, tissue will be separated and recombined in all 4 possible combinations: epi+/mes+, epi-/mes-, epi+/mes-, epi-/mes+ (+, target gene status). Tissue recombinants will be grown in athymic mice. Effects of hormone treatments will be tested using tritiated thymidine incorporation or mitotic index as the endpoint. If hypothesis 1 proves correct, this will be a novel demonstration of hormonal regulation via an epithelium-to-stroma interaction, thereby leading to a new concept of hormone action in steroid-responsive organs. If IGF-I proves critical for tissue interactions it will be the first paracrine factor to be definitively identified as a mediator of steroid action in the uterus.