TISSUE INTERACTIONS AND HORMONAL RESPONSES IN THE UTERUS

描述：（改编自申请人摘要）了解组织如何 影响生理学的相互作用对于理解 经尿道调节的器官。在子宫中，组织相互作用介导类固醇 激素效应，在早孕事件中发挥关键作用。虽然 雌激素调节间质-上皮细胞方向的细胞信号传导， 子宫，介导这种效应的旁分泌因子尚未确定。还有， 在相互方向上的途径的激素调节还没有被 研究了在人类和啮齿类动物中，雌激素刺激孕酮 支配子宫引起子宫内膜间质增生。提出 研究将验证这一假设：1）孕激素和雌激素的启动 子宫间质中细胞增殖的诱导间接发生 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)IGF-I是一种旁分泌介质， 子宫内的类固醇作用。将使用组织来检验假设 在异种移植物中生长的重组。子宫上皮和间充质 (mes)将来自新生野生型小鼠，ER α敲除（ER α KO）小鼠、PR敲除（PRKO）小鼠或IGF-I敲除小鼠。这些淘汰赛 选择模型是因为：ER α KO小鼠子宫显示无生长反应 雌二醇刺激，表明它缺乏任何促进生长的 ER; PRKO小鼠子宫对孕酮/雌激素无间质反应 在IGF-I敲除小鼠子宫中， 雌激素刺激的细胞停滞在G2期。具体目标是：1. 确定类固醇受体介导事件的组织特异性 调节细胞增殖。2.确定组织特异性 IGF-I在类固醇诱导的增殖中的介导表达 子宫对于每种类型的敲除动物，将分离组织， 以所有4种可能的组合重组：epi+/mes+，epi-/mes-，epi+/mes-， epi-/mes+（+，靶基因状态）。组织重组体将在无胸腺 小鼠将使用氚化胸苷测试激素治疗的效果 掺入或有丝分裂指数作为终点。如果假设1是正确的， 这将是一个新的证明激素调节通过一个 上皮-间质相互作用，从而导致激素的新概念 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 这将是第一个旁分泌因子， 被鉴定为子宫内类固醇作用的介质。

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.