HBEGF - A Role In Human Implantation

HBEGF - 在人体植入中的作用

• 批准号: 6787231
• 负责人: RICHARD E LEACH
• 金额: $ 10.3万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2004-06-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787231
• 关键词: antisense nucleic acid; biological signal transduction; cell differentiation; cell proliferation; embryo implantation; endometrium; epidermal growth factor; epithelium; estrogens; gene expression; growth factor receptors; hormone regulation /control mechanism; human tissue; immunocytochemistry; in situ hybridization; in vitro fertilization; messenger RNA; mixed tissue /cell culture; northern blottings; oligonucleotides; phosphorylation; progesterone; protein structure function; receptor expression; trophoblast; western blottings

DESCRIPTION: (Scanned from the applicant's abstract) The steroid-regulated Epidermal Growth Factor (EGF) family and their receptors (HERs) are expressed in the endometrium during implantation in specific spatiotemporal patterns. While there is a well-developed body of knowledge regarding the altered expression of these proteins and adverse effects on implantation in rodents, their expression patterns have not been comprehensively studied in humans during the endometrial cycle and implantation, nor is it known how the hormonal manipulations used during in vitro fertilization (IVF) alter their expression patterns. Our central hypothesis is that the synchronous development of endometrium and invasive trophoblast during early pregnancy is coordinated through the activities of EGF family growth factors, which are expressed in a steroid-dependent, spatiotemporal pattern. Interruption of these signaling pathways by an altered steroid state found during IVF procedures will impact significantly on implantation rates. We will compare the spatiotemporal expression patterns of EGF family growth factors and HER receptor subtypes in endometrial biopsy specimens obtained from women undergoing controlled ovarian hyperstimulation with gonadotropins for the purpose of oocyte donation. We will determine how estrogen and/or progesterone regulate EGF family growth factors and HER gene expression in isolated and co-cultured human uterine epithelial and stromal cells to identify how the Hyperestrogenic State alters this expression. With this information in hand we will determine the effect of candidate EGF family growth factors determined above on specific HER-mediated signaling on trophoblast cell proliferation and invasiveness using in vitro cultured cytotrophoblast cells. Our hypothesis predicts that trophoblast proliferation and differentiation are promoted in a ligand and receptor-specific manner. At the conclusion of this proposed research we will know the effect of hormonal changes found during IVF on EGF family growth factors and their receptors. Further, we will know the effect of this altered expression on trophoblast function. This information will provide mechanistic based strategies to correct the altered endometrial changes associated with IVF treatment. This information in turn can be used in the future to test IVF ovulation induction protocols to improve implantation rates.

描述：（从申请人的摘要中扫描）类固醇调节的 表达表皮生长因子 (EGF) 家族及其受体 (HER) 在以特定时空模式着床期间子宫内膜中。 虽然关于改变的知识已经有一个完善的体系 这些蛋白质的表达以及对啮齿动物植入的不利影响， 它们的表达模式尚未在人类中得到全面研究 在子宫内膜周期和着床期间，也不知道荷尔蒙如何 体外受精（IVF）过程中使用的操作改变了它们的表达 模式。我们的中心假设是同步发展 妊娠早期子宫内膜和侵袭性滋养层是协调的 通过 EGF 家族生长因子的活性，这些生长因子以 类固醇依赖性时空模式。中断这些信号 IVF 过程中发现的类固醇状态改变的途径将影响 对植入率有显着影响。我们将在时空上进行比较 EGF家族生长因子和HER受体亚型的表达模式 子宫内膜活检标本取自接受卵巢控制的女性 为了卵母细胞捐赠的目的而过度刺激促性腺激素。我们将 确定雌激素和/或孕激素如何调节 EGF 家族生长因子 和 HER 基因在分离和共培养的人子宫上皮中的表达 和基质细胞来确定高雌激素状态如何改变这一点 表达。有了这些信息，我们将确定效果 上面确定的候选 EGF 家族生长因子对特定 HER 介导的 体外滋养层细胞增殖和侵袭性信号转导 培养的细胞滋养层细胞。我们的假设预测滋养层 配体中促进增殖和分化 受体特异性方式。在这项拟议的研究结束时，我们将 了解 IVF 期间发现的荷尔蒙变化对 EGF 家族成长的影响 因子及其受体。此外，我们将知道这种改变的效果 滋养层功能的表达。该信息将提供机械 基于策略来纠正与 IVF 相关的子宫内膜变化 治疗。这些信息将来可以用来测试 IVF 诱导排卵方案以提高着床率。