FUNCTION OF HB/EGF IN UTERINE STROMAL CELLS

HB/EGF 在子宫基质细胞中的功能

• 批准号: 2889538
• 负责人: JOY I MULHOLLAND
• 金额: $ 24.5万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889538
• 关键词: antisense nucleic acid; cell differentiation; cell proliferation; connective tissue cells; decidua; epidermal growth factor; estrogens; human tissue; laboratory rat; progesterone; protein structure function; uterus; vascular endothelial growth factors

Uterine dysfunction and disease often result from the disruption of regulated cell proliferation. As examples, endometrial carcinoma, endometrosis, and leiomyoma are all characterized by abnormal cell proliferation. In addition, insufficient or asynchronous endometrial proliferation and development is a frequent cause of infertility. If cell or tissue-specific steps in the regulation of uterine cell proliferation were known, uterine-specific regulatory molecules, could serve as the basis of targeted therapies to control proliferation and differentiation in uterine disease. As a result, side-effects which result from current therapies could be avoided. Progesterone is required to support both proliferation and differentiation (decidualization) of uterine stromal cells, but very little is known of the molecular pathways stimulated by progesterone which lead to mitosis or decidualization. We have demonstrated that heparin-binding epidermal growth factor (HB-EGF) expression is stimulated by progesterone in uterine stromal cells and that inhibiting HB-EGF function also inhibits decidualization. Therefore, progesterone and HB-EGF are the only molecules which have been demonstrated to be essential for decidualization. The proposed research project is designed to elucidate the mechanisms through which HB-EGf regulates the molecular pathway leading to uterine stromal cell proliferation, and determine how proliferation controls decidualization. Our project will test the hypothesis that decidualization is dependent on progestrone-induced stroma cell proliferation, which is mediated by HB-EGF. Specific Aim 1 will test a hypothetical proliferation pathway to determine how HB-EGF regulates stromal cell proliferation, how HB-EGF itself is regulated in this pathway, and what other proteins are essential for stromal cell proliferation. Specific Aim 2 will define steps in the proliferation pathway which are essential for decidualization by blocking specific phases of the uterine stromal cell cycle. Specific Aim 3 will test a model proliferation pathway in vivo and identify additional protein targets for therapeutic intervention. The resulting model of the molecular pathway for uterine stromal cell proliferation and decidualization will provide a basic foundation for the development of selective, targeted, therapies for uterine diseases derived from unregulated cell proliferation.

子宫功能障碍和疾病通常是由于子宫功能紊乱造成的。 调节细胞增殖。 例如，子宫内膜癌、 子宫内膜异位症和平滑肌瘤均以异常细胞为特征 增殖。 此外，子宫内膜不足或不同步 增殖和发育是不孕症的常见原因。 如果 子宫细胞调节中的细胞或组织特异性步骤 众所周知，子宫特异性调节分子可以 作为控制增殖和靶向治疗的基础 子宫疾病的鉴别诊断。 结果，副作用 目前治疗的结果是可以避免的。需要黄体酮 支持增殖和分化（蜕膜化） 子宫基质细胞，但对其分子机制知之甚少 黄体酮刺激的途径导致有丝分裂或 蜕膜化。 我们已经证明，肝素结合表皮 生长因子 (HB-EGF) 的表达受黄体酮的刺激 子宫基质细胞，抑制 HB-EGF 功能也会抑制 蜕膜化。 因此，黄体酮和HB-EGF是唯一的选择。 已被证明对生命至关重要的分子 蜕膜化。 拟议的研究项目旨在阐明 HB-EGf 调节分子途径的机制 导致子宫基质细胞增殖，并确定如何 增殖控制蜕膜化。 我们的项目将测试 假设蜕膜化依赖于孕酮诱导 基质细胞增殖，由 HB-EGF 介导。 具体目标 1 将测试假设的增殖途径以确定 HB-EGF 如何 调节基质细胞增殖，HB-EGF 本身如何在 该途径以及其他哪些蛋白质对于基质细胞至关重要 增殖。 具体目标 2 将定义扩散步骤 通过阻断特定途径对于蜕膜化至关重要 子宫基质细胞周期的各个阶段。具体目标 3 将测试 体内模型增殖途径并鉴定其他蛋白质 治疗干预的目标。 由此产生的模型 子宫基质细胞增殖的分子途径 蜕膜化将为发育提供基本基础 针对子宫疾病的选择性、靶向治疗 不受调节的细胞增殖。